Skip to main content

Advertisement

Log in

Pro- and antitumor effects of mitochondrial reactive oxygen species

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

In cancer, mitochondrial functions are commonly altered. Directly involved in metabolic reprogramming, mitochondrial plasticity confers to cancer cells a high degree of adaptability to a wide range of stresses and to the harsh tumor microenvironment. Lack of nutrients or oxygen caused by altered perfusion, metabolic needs of proliferating cells, co-option of the microenvironment, control of the immune system, cell migration and metastasis, and evasion of exogenous stress (e.g., chemotherapy) are all, at least in part, influenced by mitochondria. Mitochondria are undoubtedly one of the key contributors to cancer development and progression. Understanding their protumoral (dys)functions may pave the way to therapeutic strategies capable of turning them into innocent entities. Here, we will focus on the production and detoxification of mitochondrial reactive oxygen species (mtROS), on their impact on tumorigenesis (genetic, prosurvival, and microenvironmental effects and their involvement in autophagy), and on tumor metastasis. We will also summarize the latest therapeutic approaches involving mtROS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gaude, E., & Frezza, C. (2014). Defects in mitochondrial metabolism and cancer. Cancer & Metabolism, 2, 10. https://doi.org/10.1186/2049-3002-2-10.

    Article  Google Scholar 

  2. Sabharwal, S. S., & Schumacker, P. T. (2014). Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nature Reviews. Cancer, 14(11), 709–721. https://doi.org/10.1038/nrc3803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Corbet, C., & Feron, O. (2017). Tumour acidosis: from the passenger to the driver's seat. Nature Reviews. Cancer, 17(10), 577–593. https://doi.org/10.1038/nrc.2017.77.

    Article  CAS  PubMed  Google Scholar 

  4. Justus, C. R., Sanderlin, E. J., & Yang, L. V. (2015). Molecular connections between cancer cell metabolism and the tumor microenvironment. International Journal of Molecular Sciences, 16(5), 11055–11086. https://doi.org/10.3390/ijms160511055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Corbet, C., Pinto, A., Martherus, R., Santiago de Jesus, J. P., Polet, F., & Feron, O. (2016). Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metabolism, 24(2), 311–323. https://doi.org/10.1016/j.cmet.2016.07.003.

    Article  CAS  PubMed  Google Scholar 

  6. Riemann, A., Schneider, B., Gundel, D., Stock, C., Gekle, M., & Thews, O. (2016). Acidosis promotes metastasis formation by enhancing tumor cell motility. Advances in Experimental Medicine and Biology, 876, 215–220. https://doi.org/10.1007/978-1-4939-3023-4_27.

    Article  CAS  PubMed  Google Scholar 

  7. Gupta, S. C., Singh, R., Pochampally, R., Watabe, K., & Mo, Y. Y. (2014). Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-kappaB pathway. Oncotarget, 5(23), 12070–12082. https://doi.org/10.18632/oncotarget.2514.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Murphy, M. P. (2009). How mitochondria produce reactive oxygen species. The Biochemical Journal, 417(1), 1–13. https://doi.org/10.1042/bj20081386.

    Article  CAS  PubMed  Google Scholar 

  9. Sena, L. A., & Chandel, N. S. (2012). Physiological roles of mitochondrial reactive oxygen species. Molecular Cell, 48(2), 158–167. https://doi.org/10.1016/j.molcel.2012.09.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muller, F. L., Liu, Y., & Van Remmen, H. (2004). Complex III releases superoxide to both sides of the inner mitochondrial membrane. The Journal of Biological Chemistry, 279(47), 49064–49073. https://doi.org/10.1074/jbc.M407715200.

    Article  CAS  PubMed  Google Scholar 

  11. Wellen, K. E., & Thompson, C. B. (2010). Cellular metabolic stress: considering how cells respond to nutrient excess. Molecular Cell, 40(2), 323–332. https://doi.org/10.1016/j.molcel.2010.10.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Khacho, M., Tarabay, M., Patten, D., Khacho, P., MacLaurin, J. G., Guadagno, J., et al. (2014). Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival. Nature Communications, 5, 3550. https://doi.org/10.1038/ncomms4550.

    Article  CAS  PubMed  Google Scholar 

  13. Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., et al. (2005). Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metabolism, 1(6), 401–408. https://doi.org/10.1016/j.cmet.2005.05.001.

    Article  CAS  PubMed  Google Scholar 

  14. Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., et al. (2000). Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. The Journal of Biological Chemistry, 275(33), 25130–25138. https://doi.org/10.1074/jbc.M001914200.

    Article  CAS  PubMed  Google Scholar 

  15. Beckman, J. S., & Koppenol, W. H. (1996). Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. The American Journal of Physiology, 271(5 Pt 1), C1424–C1437. https://doi.org/10.1152/ajpcell.1996.271.5.C1424.

    Article  CAS  PubMed  Google Scholar 

  16. Winterbourn, C. C., & Metodiewa, D. (1999). Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radical Biology & Medicine, 27(3–4), 322–328.

    Article  CAS  Google Scholar 

  17. Quinlan, C. L., Goncalves, R. L., Hey-Mogensen, M., Yadava, N., Bunik, V. I., & Brand, M. D. (2014). The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. The Journal of Biological Chemistry, 289(12), 8312–8325. https://doi.org/10.1074/jbc.M113.545301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goncalves, R. L., Bunik, V. I., & Brand, M. D. (2016). Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex. Free Radical Biology & Medicine, 91, 247–255. https://doi.org/10.1016/j.freeradbiomed.2015.12.020.

    Article  CAS  Google Scholar 

  19. Mari, M., Morales, A., Colell, A., Garcia-Ruiz, C., & Fernandez-Checa, J. C. (2009). Mitochondrial glutathione, a key survival antioxidant. Antioxidants & Redox Signaling, 11(11), 2685–2700. https://doi.org/10.1089/ars.2009.2695.

    Article  CAS  Google Scholar 

  20. Chung, W. J., Lyons, S. A., Nelson, G. M., Hamza, H., Gladson, C. L., Gillespie, G. Y., et al. (2005). Inhibition of cystine uptake disrupts the growth of primary brain tumors. The Journal of Neuroscience, 25(31), 7101–7110. https://doi.org/10.1523/JNEUROSCI.5258-04.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, W., Trachootham, D., Liu, J., Chen, G., Pelicano, H., Garcia-Prieto, C., et al. (2012). Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nature Cell Biology, 14(3), 276–286. https://doi.org/10.1038/ncb2432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cramer, S. L., Saha, A., Liu, J., Tadi, S., Tiziani, S., Yan, W., et al. (2017). Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nature Medicine, 23(1), 120–127. https://doi.org/10.1038/nm.4232.

    Article  CAS  PubMed  Google Scholar 

  23. Maddocks, O. D., Berkers, C. R., Mason, S. M., Zheng, L., Blyth, K., Gottlieb, E., et al. (2013). Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature, 493(7433), 542–546. https://doi.org/10.1038/nature11743.

    Article  CAS  PubMed  Google Scholar 

  24. Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology, 53, 401–426. https://doi.org/10.1146/annurev-pharmtox-011112-140320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Szatrowski, T. P., & Nathan, C. F. (1991). Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Research, 51(3), 794–798.

    CAS  PubMed  Google Scholar 

  26. Assi, M., & Rebillard, A. (2016). The Janus-faced role of antioxidants in cancer cachexia: new insights on the established concepts. Oxidative Medicine and Cellular Longevity, 2016, 9579868. https://doi.org/10.1155/2016/9579868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Govindarajan, B., Sligh, J. E., Vincent, B. J., Li, M., Canter, J. A., Nickoloff, B. J., et al. (2007). Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. The Journal of Clinical Investigation, 117(3), 719–729. https://doi.org/10.1172/jci30102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ferraro, D., Corso, S., Fasano, E., Panieri, E., Santangelo, R., Borrello, S., et al. (2006). Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene, 25(26), 3689–3698. https://doi.org/10.1038/sj.onc.1209409.

    Article  CAS  PubMed  Google Scholar 

  29. Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., Fata, J. E., et al. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436(7047), 123–127. https://doi.org/10.1038/nature03688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Girnun, G. D. (2012). The diverse role of the PPARgamma coactivator 1 family of transcriptional coactivators in cancer. Seminars in Cell & Developmental Biology, 23(4), 381–388. https://doi.org/10.1016/j.semcdb.2012.01.007.

    Article  CAS  Google Scholar 

  31. LeBleu, V. S., O'Connell, J. T., Gonzalez Herrera, K. N., Wikman, H., Pantel, K., Haigis, M. C., et al. (2014). PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature Cell Biology, 16(10), 992–1003, 1001-1015. https://doi.org/10.1038/ncb3039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, E. I., Hewel, J., Krueger, J. S., Tiraby, C., Weber, M. R., Kralli, A., et al. (2007). Adaptation of energy metabolism in breast cancer brain metastases. Cancer Research, 67(4), 1472–1486. https://doi.org/10.1158/0008-5472.CAN-06-3137.

    Article  CAS  PubMed  Google Scholar 

  33. Torrano, V., Valcarcel-Jimenez, L., Cortazar, A. R., Liu, X., Urosevic, J., Castillo-Martin, M., et al. (2016). The metabolic co-regulator PGC1alpha suppresses prostate cancer metastasis. Nature Cell Biology, 18(6), 645–656. https://doi.org/10.1038/ncb3357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luo, C., Lim, J. H., Lee, Y., Granter, S. R., Thomas, A., Vazquez, F., et al. (2016). A PGC1alpha-mediated transcriptional axis suppresses melanoma metastasis. Nature, 537(7620), 422–426. https://doi.org/10.1038/nature19347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jager, S., et al. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2), 397–408. https://doi.org/10.1016/j.cell.2006.09.024.

    Article  CAS  PubMed  Google Scholar 

  36. Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., et al. (2012). A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell, 151(6), 1319–1331. https://doi.org/10.1016/j.cell.2012.10.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Esparza-Molto, P. B., & Cuezva, J. M. (2018). The role of mitochondrial H(+)-ATP synthase in cancer. Frontiers in Oncology, 8, 53. https://doi.org/10.3389/fonc.2018.00053.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Santacatterina, F., Sanchez-Cenizo, L., Formentini, L., Mobasher, M. A., Casas, E., Rueda, C. B., et al. (2016). Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. Oncotarget, 7(1), 490–508. https://doi.org/10.18632/oncotarget.6357.

    Article  PubMed  Google Scholar 

  39. Alexeyev, M., Shokolenko, I., Wilson, G., & LeDoux, S. (2013). The maintenance of mitochondrial DNA integrity—critical analysis and update. Cold Spring Harbor Perspectives in Biology, 5(5), a012641. https://doi.org/10.1101/cshperspect.a012641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Canter, J. A., Kallianpur, A. R., Parl, F. F., & Millikan, R. C. (2005). Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Research, 65(17), 8028–8033. https://doi.org/10.1158/0008-5472.Can-05-1428.

    Article  CAS  PubMed  Google Scholar 

  41. Darvishi, K., Sharma, S., Bhat, A. K., Rai, E., & Bamezai, R. N. (2007). Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Letters, 249(2), 249–255. https://doi.org/10.1016/j.canlet.2006.09.005.

    Article  CAS  PubMed  Google Scholar 

  42. Ebner, S., Lang, R., Mueller, E. E., Eder, W., Oeller, M., Moser, A., et al. (2011). Mitochondrial haplogroups, control region polymorphisms and malignant melanoma: a study in middle European Caucasians. PLoS One, 6(12), e27192. https://doi.org/10.1371/journal.pone.0027192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Polyak, K., Li, Y., Zhu, H., Lengauer, C., Willson, J. K., Markowitz, S. D., et al. (1998). Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genetics, 20(3), 291–293. https://doi.org/10.1038/3108.

    Article  CAS  PubMed  Google Scholar 

  44. Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., Imanishi, H., et al. (2008). ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science, 320(5876), 661–664. https://doi.org/10.1126/science.1156906.

    Article  CAS  PubMed  Google Scholar 

  45. Ishikawa, K., Hashizume, O., Koshikawa, N., Fukuda, S., Nakada, K., Takenaga, K., et al. (2008). Enhanced glycolysis induced by mtDNA mutations does not regulate metastasis. FEBS Letters, 582(23–24), 3525–3530. https://doi.org/10.1016/j.febslet.2008.09.024.

    Article  CAS  PubMed  Google Scholar 

  46. Petros, J. A., Baumann, A. K., Ruiz-Pesini, E., Amin, M. B., Sun, C. Q., Hall, J., et al. (2005). mtDNA mutations increase tumorigenicity in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 102(3), 719–724. https://doi.org/10.1073/pnas.0408894102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Singh, R. K., Srivastava, A., Kalaiarasan, P., Manvati, S., Chopra, R., & Bamezai, R. N. (2014). mtDNA germ line variation mediated ROS generates retrograde signaling and induces pro-cancerous metabolic features. Science Reports, 4, 6571. https://doi.org/10.1038/srep06571.

    Article  CAS  Google Scholar 

  48. Dasgupta, S., Hoque, M. O., Upadhyay, S., & Sidransky, D. (2008). Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer Research, 68(3), 700–706. https://doi.org/10.1158/0008-5472.Can-07-5532.

    Article  CAS  PubMed  Google Scholar 

  49. Morais, R., Zinkewich-Peotti, K., Parent, M., Wang, H., Babai, F., & Zollinger, M. (1994). Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. Cancer Research, 54(14), 3889–3896.

    CAS  PubMed  Google Scholar 

  50. Cavalli, L. R., Varella-Garcia, M., & Liang, B. C. (1997). Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth & Differentiation, 8(11), 1189–1198.

    CAS  Google Scholar 

  51. Gasparre, G., Hervouet, E., de Laplanche, E., Demont, J., Pennisi, L. F., Colombel, M., et al. (2008). Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma. Human Molecular Genetics, 17(7), 986–995. https://doi.org/10.1093/hmg/ddm371.

    Article  CAS  PubMed  Google Scholar 

  52. Gasparre, G., Romeo, G., Rugolo, M., & Porcelli, A. M. (2011). Learning from oncocytic tumors: why choose inefficient mitochondria? Biochimica et Biophysica Acta, 1807(6), 633–642. https://doi.org/10.1016/j.bbabio.2010.08.006.

    Article  CAS  PubMed  Google Scholar 

  53. Mayr, J. A., Meierhofer, D., Zimmermann, F., Feichtinger, R., Kogler, C., Ratschek, M., et al. (2008). Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma. Clinical Cancer Research, 14(8), 2270–2275. https://doi.org/10.1158/1078-0432.Ccr-07-4131.

    Article  CAS  PubMed  Google Scholar 

  54. Tallini, G. (1998). Oncocytic tumours. Virchows Archiv, 433(1), 5–12.

    Article  CAS  PubMed  Google Scholar 

  55. Gasparre, G., Kurelac, I., Capristo, M., Iommarini, L., Ghelli, A., Ceccarelli, C., et al. (2011). A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an oncojanus function. Cancer Research, 71(19), 6220–6229. https://doi.org/10.1158/0008-5472.Can-11-1042.

    Article  CAS  PubMed  Google Scholar 

  56. Oliva, C. R., Nozell, S. E., Diers, A., McClugage, S. G., 3rd, Sarkaria, J. N., Markert, J. M., et al. (2010). Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain. The Journal of Biological Chemistry, 285(51), 39759–39767. https://doi.org/10.1074/jbc.M110.147504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Griguer, C. E., Cantor, A. B., Fathallah-Shaykh, H. M., Gillespie, G. Y., Gordon, A. S., Markert, J. M., et al. (2013). Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme. PLoS One, 8(4), e61035. https://doi.org/10.1371/journal.pone.0061035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Oliva, C. R., Moellering, D. R., Gillespie, G. Y., & Griguer, C. E. (2011). Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One, 6(9), e24665. https://doi.org/10.1371/journal.pone.0024665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bell, E. L., Klimova, T. A., Eisenbart, J., Moraes, C. T., Murphy, M. P., Budinger, G. R., et al. (2007). The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. The Journal of Cell Biology, 177(6), 1029–1036. https://doi.org/10.1083/jcb.200609074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brunelle, J. K., Bell, E. L., Quesada, N. M., Vercauteren, K., Tiranti, V., Zeviani, M., et al. (2005). Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metabolism, 1(6), 409–414. https://doi.org/10.1016/j.cmet.2005.05.002.

    Article  CAS  PubMed  Google Scholar 

  61. Mansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., et al. (2005). Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metabolism, 1(6), 393–399. https://doi.org/10.1016/j.cmet.2005.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. De Saedeleer, C. J., Porporato, P. E., Copetti, T., Perez-Escuredo, J., Payen, V. L., Brisson, L., et al. (2014). Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene, 33(31), 4060–4068. https://doi.org/10.1038/onc.2013.454.

    Article  CAS  PubMed  Google Scholar 

  63. Graham, N. A., Tahmasian, M., Kohli, B., Komisopoulou, E., Zhu, M., Vivanco, I., et al. (2012). Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Molecular Systems Biology, 8, 589. https://doi.org/10.1038/msb.2012.20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nazarewicz, R. R., Dikalova, A. E., Bikineyeva, A., & Dikalov, S. I. (2013). Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress. American Journal of Physiology. Heart and Circulatory Physiology, 305(8), H1131–H1140. https://doi.org/10.1152/ajpheart.00063.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dikalova, A. E., Bikineyeva, A. T., Budzyn, K., Nazarewicz, R. R., McCann, L., Lewis, W., et al. (2010). Therapeutic targeting of mitochondrial superoxide in hypertension. Circulation Research, 107(1), 106–116. https://doi.org/10.1161/circresaha.109.214601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Molognoni, F., de Melo, F. H., da Silva, C. T., & Jasiulionis, M. G. (2013). Ras and Rac1, frequently mutated in melanomas, are activated by superoxide anion, modulate Dnmt1 level and are causally related to melanocyte malignant transformation. PLoS One, 8(12), e81937. https://doi.org/10.1371/journal.pone.0081937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Imhoff, B. R., & Hansen, J. M. (2009). Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species. The Biochemical Journal, 424(3), 491–500. https://doi.org/10.1042/bj20091286.

    Article  CAS  PubMed  Google Scholar 

  68. Korshunov, S. S., Skulachev, V. P., & Starkov, A. A. (1997). High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Letters, 416(1), 15–18.

    Article  CAS  PubMed  Google Scholar 

  69. Skulachev, V. P. (1998). Uncoupling: new approaches to an old problem of bioenergetics. Biochimica et Biophysica Acta, 1363(2), 100–124.

    Article  CAS  PubMed  Google Scholar 

  70. Checchetto, V., Azzolini, M., Peruzzo, R., Capitanio, P., & Leanza, L. (2018). Mitochondrial potassium channels in cell death. Biochemical and Biophysical Research Communications, 500(1), 51–58. https://doi.org/10.1016/j.bbrc.2017.06.095.

    Article  CAS  PubMed  Google Scholar 

  71. Malinska, D., Mirandola, S. R., & Kunz, W. S. (2010). Mitochondrial potassium channels and reactive oxygen species. FEBS Letters, 584(10), 2043–2048. https://doi.org/10.1016/j.febslet.2010.01.013.

    Article  CAS  PubMed  Google Scholar 

  72. Lluis, J. M., Buricchi, F., Chiarugi, P., Morales, A., & Fernandez-Checa, J. C. (2007). Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Research, 67(15), 7368–7377. https://doi.org/10.1158/0008-5472.Can-07-0515.

    Article  CAS  PubMed  Google Scholar 

  73. DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., et al. (2011). Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature, 475(7354), 106–109. https://doi.org/10.1038/nature10189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., et al. (2010). Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America, 107(19), 8788–8793. https://doi.org/10.1073/pnas.1003428107.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Anastasiou, D., Poulogiannis, G., Asara, J. M., Boxer, M. B., Jiang, J. K., Shen, M., et al. (2011). Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science, 334(6060), 1278–1283. https://doi.org/10.1126/science.1211485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kong, H., & Chandel, N. S. (2018). Regulation of redox balance in cancer and T cells. The Journal of Biological Chemistry, 293(20), 7499–7507. https://doi.org/10.1074/jbc.TM117.000257.

    Article  CAS  PubMed  Google Scholar 

  77. Di Marcantonio, D., Martinez, E., Sidoli, S., Vadaketh, J., Nieborowska-Skorska, M., Gupta, A., et al. (2018). Protein kinase C epsilon is a key regulator of mitochondrial redox homeostasis in acute myeloid leukemia. Clinical Cancer Research, 24(3), 608–618. https://doi.org/10.1158/1078-0432.Ccr-17-2684.

    Article  PubMed  Google Scholar 

  78. Karnati, S., Luers, G., Pfreimer, S., & Baumgart-Vogt, E. (2013). Mammalian SOD2 is exclusively located in mitochondria and not present in peroxisomes. Histochemistry and Cell Biology, 140(2), 105–117. https://doi.org/10.1007/s00418-013-1099-4.

    Article  CAS  PubMed  Google Scholar 

  79. Sreevalsan, S., & Safe, S. (2013). Reactive oxygen species and colorectal cancer. Current Colorectal Cancer Reports, 9(4), 350–357. https://doi.org/10.1007/s11888-013-0190-5.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Assi, M. (2017). The differential role of reactive oxygen species in early and late stages of cancer. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 313(6), R646–r653. https://doi.org/10.1152/ajpregu.00247.2017.

    Article  CAS  PubMed  Google Scholar 

  81. Chen, P., Luo, X., Nie, P., Wu, B., Xu, W., Shi, X., et al. (2017). CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Free Radical Biology & Medicine, 104, 280–297. https://doi.org/10.1016/j.freeradbiomed.2017.01.033.

    Article  CAS  Google Scholar 

  82. Kang, K. A., Zhang, R., Kim, G. Y., Bae, S. C., & Hyun, J. W. (2012). Epigenetic changes induced by oxidative stress in colorectal cancer cells: methylation of tumor suppressor RUNX3. Tumour Biology, 33(2), 403–412. https://doi.org/10.1007/s13277-012-0322-6.

    Article  CAS  PubMed  Google Scholar 

  83. Ott, M., Robertson, J. D., Gogvadze, V., Zhivotovsky, B., & Orrenius, S. (2002). Cytochrome c release from mitochondria proceeds by a two-step process. Proceedings of the National Academy of Sciences of the United States of America, 99(3), 1259–1263. https://doi.org/10.1073/pnas.241655498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., et al. (1995). Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. The Journal of Experimental Medicine, 182(2), 367–377.

    Article  CAS  PubMed  Google Scholar 

  85. Thorpe, G. W., Reodica, M., Davies, M. J., Heeren, G., Jarolim, S., Pillay, B., et al. (2013). Superoxide radicals have a protective role during H2O2 stress. Molecular Biology of the Cell, 24(18), 2876–2884. https://doi.org/10.1091/mbc.E13-01-0052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. De Haes, W., Frooninckx, L., Van Assche, R., Smolders, A., Depuydt, G., Billen, J., et al. (2014). Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proceedings of the National Academy of Sciences of the United States of America, 111(24), E2501–E2509. https://doi.org/10.1073/pnas.1321776111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zarse, K., Schmeisser, S., Groth, M., Priebe, S., Beuster, G., Kuhlow, D., et al. (2012). Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metabolism, 15(4), 451–465. https://doi.org/10.1016/j.cmet.2012.02.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dewaele, M., Maes, H., & Agostinis, P. (2010). ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy, 6(7), 838–854.

    Article  CAS  PubMed  Google Scholar 

  89. White, E. (2012). Deconvoluting the context-dependent role for autophagy in cancer. Nature Reviews. Cancer, 12(6), 401–410. https://doi.org/10.1038/nrc3262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., & Schumacker, P. T. (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proceedings of the National Academy of Sciences of the United States of America, 95(20), 11715–11720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chang, J., Jung, H. J., Jeong, S. H., Kim, H. K., Han, J., & Kwon, H. J. (2014). A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species. Biochemical and Biophysical Research Communications, 455(3–4), 290–297. https://doi.org/10.1016/j.bbrc.2014.11.005.

    Article  CAS  PubMed  Google Scholar 

  92. Masson, N., Singleton, R. S., Sekirnik, R., Trudgian, D. C., Ambrose, L. J., Miranda, M. X., et al. (2012). The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Reports, 13(3), 251–257. https://doi.org/10.1038/embor.2012.9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fukuda, R., Zhang, H., Kim, J. W., Shimoda, L., Dang, C. V., & Semenza, G. L. (2007). HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell, 129(1), 111–122. https://doi.org/10.1016/j.cell.2007.01.047.

    Article  CAS  PubMed  Google Scholar 

  94. Kim, J. W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3(3), 177–185. https://doi.org/10.1016/j.cmet.2006.02.002.

    Article  CAS  PubMed  Google Scholar 

  95. Semenza, G. L., Roth, P. H., Fang, H. M., & Wang, G. L. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. The Journal of Biological Chemistry, 269(38), 23757–23763.

    CAS  PubMed  Google Scholar 

  96. Jurica, M. S., Mesecar, A., Heath, P. J., Shi, W., Nowak, T., & Stoddard, B. L. (1998). The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure, 6(2), 195–210.

    Article  CAS  PubMed  Google Scholar 

  97. Dombrauckas, J. D., Santarsiero, B. D., & Mesecar, A. D. (2005). Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry, 44(27), 9417–9429. https://doi.org/10.1021/bi0474923.

    Article  CAS  PubMed  Google Scholar 

  98. Bellot, G., Garcia-Medina, R., Gounon, P., Chiche, J., Roux, D., Pouyssegur, J., et al. (2009). Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Molecular and Cellular Biology, 29(10), 2570–2581. https://doi.org/10.1128/mcb.00166-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., et al. (2008). Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. The Journal of Biological Chemistry, 283(16), 10892–10903. https://doi.org/10.1074/jbc.M800102200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Keith, B., Johnson, R. S., & Simon, M. C. (2011). HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature Reviews. Cancer, 12(1), 9–22. https://doi.org/10.1038/nrc3183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wen, J., Wang, Y., Gao, C., Zhang, G., You, Q., Zhang, W., et al. (2018). Helicobacter pylori infection promotes Aquaporin 3 expression via the ROS-HIF-1alpha-AQP3-ROS loop in stomach mucosa: a potential novel mechanism for cancer pathogenesis. Oncogene, 37(26), 3549–3561. https://doi.org/10.1038/s41388-018-0208-1.

    Article  CAS  PubMed  Google Scholar 

  102. Zhao, X.-L., & Yu, C.-Z. (2018). Vosaroxin induces mitochondrial dysfunction and apoptosis in cervical cancer HeLa cells: involvement of AMPK/Sirt3/HIF-1 pathway. Chemico-Biological Interactions, 290, 57–63. https://doi.org/10.1016/j.cbi.2018.05.011.

    Article  CAS  PubMed  Google Scholar 

  103. Moeller, B. J., Richardson, R. A., & Dewhirst, M. W. (2007). Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Reviews, 26(2), 241–248. https://doi.org/10.1007/s10555-007-9056-0.

    Article  CAS  PubMed  Google Scholar 

  104. Rohwer, N., & Cramer, T. (2011). Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resistance Updates, 14(3), 191–201. https://doi.org/10.1016/j.drup.2011.03.001.

    Article  CAS  PubMed  Google Scholar 

  105. Semenza, G. L. (2012). Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends in Pharmacological Sciences, 33(4), 207–214. https://doi.org/10.1016/j.tips.2012.01.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu, T., Tang, B., & Sun, X. (2017). Development of inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Medical Journal, 58(3), 489–496. https://doi.org/10.3349/ymj.2017.58.3.489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fiaschi, T., Marini, A., Giannoni, E., Taddei, M. L., Gandellini, P., De Donatis, A., et al. (2012). Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Research, 72(19), 5130–5140. https://doi.org/10.1158/0008-5472.Can-12-1949.

    Article  CAS  PubMed  Google Scholar 

  108. Sanita, P., Capulli, M., Teti, A., Galatioto, G. P., Vicentini, C., Chiarugi, P., et al. (2014). Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer, 14, 154. https://doi.org/10.1186/1471-2407-14-154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Morselli, E., Galluzzi, L., Kepp, O., Vicencio, J. M., Criollo, A., Maiuri, M. C., et al. (2009). Anti- and pro-tumor functions of autophagy. Biochimica et Biophysica Acta, 1793(9), 1524–1532. https://doi.org/10.1016/j.bbamcr.2009.01.006.

    Article  CAS  PubMed  Google Scholar 

  110. Scherz-Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z. (2007). Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. The EMBO Journal, 26(7), 1749–1760. https://doi.org/10.1038/sj.emboj.7601623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Poillet-Perez, L., Despouy, G., Delage-Mourroux, R., & Boyer-Guittaut, M. (2015). Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biology, 4, 184–192. https://doi.org/10.1016/j.redox.2014.12.003.

    Article  CAS  PubMed  Google Scholar 

  112. Tan, A. S., Baty, J. W., Dong, L. F., Bezawork-Geleta, A., Endaya, B., Goodwin, J., et al. (2015). Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metabolism, 21(1), 81–94. https://doi.org/10.1016/j.cmet.2014.12.003.

    Article  CAS  PubMed  Google Scholar 

  113. He, X., Zhou, A., Lu, H., Chen, Y., Huang, G., Yue, X., et al. (2013). Suppression of mitochondrial complex I influences cell metastatic properties. PLoS One, 8(4), e61677. https://doi.org/10.1371/journal.pone.0061677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Comito, G., Calvani, M., Giannoni, E., Bianchini, F., Calorini, L., Torre, E., et al. (2011). HIF-1alpha stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. Free Radical Biology & Medicine, 51(4), 893–904. https://doi.org/10.1016/j.freeradbiomed.2011.05.042.

    Article  CAS  Google Scholar 

  115. Arnold, R. S., Sun, C. Q., Richards, J. C., Grigoriev, G., Coleman, I. M., Nelson, P. S., et al. (2009). Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate, 69(1), 1–11. https://doi.org/10.1002/pros.20854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Porporato, P. E., Payen, V. L., Perez-Escuredo, J., De Saedeleer, C. J., Danhier, P., Copetti, T., et al. (2014). A mitochondrial switch promotes tumor metastasis. Cell Reports, 8(3), 754–766. https://doi.org/10.1016/j.celrep.2014.06.043.

    Article  CAS  PubMed  Google Scholar 

  117. Riemann, A., Schneider, B., Gundel, D., Stock, C., Thews, O., & Gekle, M. (2014). Acidic priming enhances metastatic potential of cancer cells. Pflügers Archiv, 466(11), 2127–2138. https://doi.org/10.1007/s00424-014-1458-6.

    Article  CAS  PubMed  Google Scholar 

  118. Paoli, P., Giannoni, E., & Chiarugi, P. (2013). Anoikis molecular pathways and its role in cancer progression. Biochimica et Biophysica Acta, 1833(12), 3481–3498. https://doi.org/10.1016/j.bbamcr.2013.06.026.

    Article  CAS  PubMed  Google Scholar 

  119. Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., et al. (2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature, 527(7577), 186–191. https://doi.org/10.1038/nature15726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kamarajugadda, S., Cai, Q., Chen, H., Nayak, S., Zhu, J., He, M., et al. (2013). Manganese superoxide dismutase promotes anoikis resistance and tumor metastasis. Cell Death & Disease, 4, e504. https://doi.org/10.1038/cddis.2013.20.

    Article  CAS  Google Scholar 

  121. Lu, X., Bennet, B., Mu, E., Rabinowitz, J., & Kang, Y. (2010). Metabolomic changes accompanying transformation and acquisition of metastatic potential in a syngeneic mouse mammary tumor model. The Journal of Biological Chemistry, 285(13), 9317–9321. https://doi.org/10.1074/jbc.C110.104448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Le Gal, K., Ibrahim, M. X., Wiel, C., Sayin, V. I., Akula, M. K., Karlsson, C., et al. (2015). Antioxidants can increase melanoma metastasis in mice. Science Translational Medicine, 7(308), 308re308. https://doi.org/10.1126/scitranslmed.aad3740.

    Article  Google Scholar 

  123. Sayin, V. I., Ibrahim, M. X., Larsson, E., Nilsson, J. A., Lindahl, P., & Bergo, M. O. (2014). Antioxidants accelerate lung cancer progression in mice. Science Translational Medicine, 6(221), 221ra215. https://doi.org/10.1126/scitranslmed.3007653.

    Article  CAS  Google Scholar 

  124. Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., et al. (2007). HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell, 12(3), 230–238. https://doi.org/10.1016/j.ccr.2007.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Klein, E. A., Thompson, I. M., Jr., Tangen, C. M., Crowley, J. J., Lucia, M. S., Goodman, P. J., et al. (2011). Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 306(14), 1549–1556. https://doi.org/10.1001/jama.2011.1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hercberg, S., Galan, P., Preziosi, P., Bertrais, S., Mennen, L., Malvy, D., et al. (2004). The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Archives of Internal Medicine, 164(21), 2335–2342. https://doi.org/10.1001/archinte.164.21.2335.

    Article  CAS  PubMed  Google Scholar 

  127. Jacobs, C., Hutton, B., Ng, T., Shorr, R., & Clemons, M. (2015). Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review. Oncologist, 20(2), 210–223. https://doi.org/10.1634/theoncologist.2014-0381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bairati, I., Meyer, F., Gelinas, M., Fortin, A., Nabid, A., Brochet, F., et al. (2005). Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. Journal of Clinical Oncology, 23(24), 5805–5813. https://doi.org/10.1200/jco.2005.05.514.

    Article  CAS  PubMed  Google Scholar 

  129. Lawenda, B. D., Kelly, K. M., Ladas, E. J., Sagar, S. M., Vickers, A., & Blumberg, J. B. (2008). Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute, 100(11), 773–783. https://doi.org/10.1093/jnci/djn148.

    Article  CAS  PubMed  Google Scholar 

  130. Ozben, T. (2015). Antioxidant supplementation on cancer risk and during cancer therapy: an update. Current Topics in Medicinal Chemistry, 15(2), 170–178.

    Article  CAS  PubMed  Google Scholar 

  131. Bonner, M. Y., & Arbiser, J. L. (2014). The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer. Future Medicinal Chemistry, 6(12), 1413–1422. https://doi.org/10.4155/fmc.14.86.

    Article  CAS  PubMed  Google Scholar 

  132. Jin, H., Kanthasamy, A., Ghosh, A., Anantharam, V., Kalyanaraman, B., & Kanthasamy, A. G. (2014). Mitochondria-targeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes. Biochimica et Biophysica Acta, 1842(8), 1282–1294. https://doi.org/10.1016/j.bbadis.2013.09.007.

    Article  CAS  PubMed  Google Scholar 

  133. Chandel, N. S., & Tuveson, D. A. (2014). The promise and perils of antioxidants for cancer patients. The New England Journal of Medicine, 371(2), 177–178. https://doi.org/10.1056/NEJMcibr1405701.

    Article  CAS  PubMed  Google Scholar 

  134. Nazarewicz, R. R., Dikalova, A., Bikineyeva, A., Ivanov, S., Kirilyuk, I. A., Grigor'ev, I. A., et al. (2013). Does scavenging of mitochondrial superoxide attenuate cancer prosurvival signaling pathways? Antioxidants & Redox Signaling, 19(4), 344–349. https://doi.org/10.1089/ars.2013.5185.

    Article  CAS  Google Scholar 

  135. Cheriyath, V., Kaur, J., Davenport, A., Khalel, A., Chowdhury, N., & Gaddipati, L. (2018). G1P3 (IFI6), a mitochondrial localised antiapoptotic protein, promotes metastatic potential of breast cancer cells through mtROS. British Journal of Cancer, 119(1), 52–64. https://doi.org/10.1038/s41416-018-0137-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wang, B., Fu, J., Yu, T., Xu, A., Qin, W., Yang, Z., et al. (2017). Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice. Hepatology. https://doi.org/10.1002/hep.29518.

  137. Titova, E., Shagieva, G., Ivanova, O., Domnina, L., Domninskaya, M., Strelkova, O., et al. (2018). Mitochondria-targeted antioxidant SkQ1 suppresses fibrosarcoma and rhabdomyosarcoma tumour cell growth. Cell Cycle, 17(14), 1797–1811. https://doi.org/10.1080/15384101.2018.1496748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Aceto, N., Bardia, A., Miyamoto, D. T., Donaldson, M. C., Wittner, B. S., Spencer, J. A., et al. (2014). Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell, 158(5), 1110–1122. https://doi.org/10.1016/j.cell.2014.07.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Verrax, J., Cadrobbi, J., Marques, C., Taper, H., Habraken, Y., Piette, J., et al. (2004). Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death. Apoptosis, 9(2), 223–233. https://doi.org/10.1023/B:APPT.0000018804.26026.1a.

    Article  CAS  PubMed  Google Scholar 

  140. Verrax, J., Delvaux, M., Beghein, N., Taper, H., Gallez, B., & Buc Calderon, P. (2005). Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study. Free Radical Research, 39(6), 649–657. https://doi.org/10.1080/10715760500097906.

    Article  CAS  PubMed  Google Scholar 

  141. Verrax, J., Stockis, J., Tison, A., Taper, H. S., & Calderon, P. B. (2006). Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. Biochemical Pharmacology, 72(6), 671–680. https://doi.org/10.1016/j.bcp.2006.05.025.

    Article  CAS  PubMed  Google Scholar 

  142. Trachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., et al. (2006). Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell, 10(3), 241–252. https://doi.org/10.1016/j.ccr.2006.08.009.

    Article  CAS  PubMed  Google Scholar 

  143. Stacpoole, P. W. (2017). Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. Journal of the National Cancer Institute, 109(11). https://doi.org/10.1093/jnci/djx071.

  144. Shaw, A. T., Winslow, M. M., Magendantz, M., Ouyang, C., Dowdle, J., Subramanian, A., et al. (2011). Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proceedings of the National Academy of Sciences of the United States of America, 108(21), 8773–8778. https://doi.org/10.1073/pnas.1105941108.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., et al. (2007). RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature, 447(7146), 864–868. https://doi.org/10.1038/nature05859.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Hou, X. S., Wang, H. S., Mugaka, B. P., Yang, G. J., & Ding, Y. (2018). Mitochondria: promising organelle targets for cancer diagnosis and treatment. Biomaterials Science, 6(11), 2786–2797. https://doi.org/10.1039/c8bm00673c.

    Article  CAS  PubMed  Google Scholar 

  147. Basit, F., van Oppen, L. M., Schockel, L., Bossenbroek, H. M., van Emst-de Vries, S. E., Hermeling, J. C., et al. (2017). Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death & Disease, 8(3), e2716. https://doi.org/10.1038/cddis.2017.133.

    Article  Google Scholar 

  148. Hammerova, J., Uldrijan, S., Taborska, E., Vaculova, A. H., & Slaninova, I. (2012). Necroptosis modulated by autophagy is a predominant form of melanoma cell death induced by sanguilutine. Biological Chemistry, 393(7), 647–658. https://doi.org/10.1515/hsz-2011-0279.

    Article  CAS  PubMed  Google Scholar 

  149. Sonkusre, P., & Cameotra, S. S. (2017). Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation. Journal of Nanobiotechnology, 15(1), 43. https://doi.org/10.1186/s12951-017-0276-3.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Jung, H. S., Lee, J. H., Kim, K., Koo, S., Verwilst, P., Sessler, J. L., et al. (2017). A mitochondria-targeted cryptocyanine-based photothermogenic photosensitizer. Journal of the American Chemical Society, 139(29), 9972–9978. https://doi.org/10.1021/jacs.7b04263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jung, H. S., Han, J., Lee, J. H., Lee, J. H., Choi, J. M., Kweon, H. S., et al. (2015). Enhanced NIR radiation-triggered hyperthermia by mitochondrial targeting. Journal of the American Chemical Society, 137(8), 3017–3023. https://doi.org/10.1021/ja5122809.

    Article  CAS  PubMed  Google Scholar 

  152. Chakrabortty, S., Agrawalla, B. K., Stumper, A., Vegi, N. M., Fischer, S., Reichardt, C., et al. (2017). Mitochondria targeted protein-ruthenium photosensitizer for efficient photodynamic applications. Journal of the American Chemical Society, 139(6), 2512–2519. https://doi.org/10.1021/jacs.6b13399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Guo, R., Peng, H., Tian, Y., Shen, S., & Yang, W. (2016). Mitochondria-targeting magnetic composite nanoparticles for enhanced phototherapy of cancer. Small, 12(33), 4541–4552. https://doi.org/10.1002/smll.201601094.

    Article  CAS  PubMed  Google Scholar 

  154. Stolik, S., Delgado, J. A., Perez, A., & Anasagasti, L. (2000). Measurement of the penetration depths of red and near infrared light in human “ex vivo” tissues. Journal of Photochemistry and Photobiology. B, 57(2–3), 90–93.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Works at authors’ labs are supported by European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 642623 RADIATE and No. 722605 TRANSMIT, the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Belgian Télévie and the Fondation Louvain (all to PS), and the Italian Ministry for University and Research (MIUR, Rita Levi-Montalcini program for young researchers 2014) to PEP. PS is a F.R.S.-FNRS Senior Research Associate. LXZ is a PhD Fellow of Marie Skłodowska-Curie grant No. 722605 TRANSMIT.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pierre Sonveaux.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Special issue:Acidosis Cancer - Robert Gillies, Guest Editor

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Payen, V.L., Zampieri, L.X., Porporato, P.E. et al. Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev 38, 189–203 (2019). https://doi.org/10.1007/s10555-019-09789-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-019-09789-2

Keywords

Navigation