Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial membrane potential and reactive oxygen species in cancer stem cells

  • Review
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Cancer stem cells (CSCs) are believed as the initiators of the occurrence, development and recurrence of malignant tumors. Targeting this unique cell population would provide a less toxic approach than regular chemotherapeutic agents that kill bulk rapid proliferating tumor cells and also normal cells which divide rapidly. To date, major research effort has been aimed at identifying and eradicating CSC population. The metabolism heterogeneity of mitochondria in CSCs shows a big promise for cancer research. Of them, mitochondrial membrane potential (Δψm), reflecting the functional status of the mitochondrion is proved to be highly related to cancer malignancy. Reactive oxygen species, mainly produced from mitochondria, are also increased in many types of cancer cells. However, their statuses in CSCs remain poorly understood. Here we shall review the mitochondrial membrane potential and reactive oxygen species of CSCs and propose the novel potential targets for cancer therapy.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768. doi:10.1038/nrc2499

    Article  CAS  PubMed  Google Scholar 

  2. Eyler CE, Rich JN (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 26(17):2839–2845. doi:10.1200/JCO.2007.15.1829

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Dayem AA, Choi HY, Kim JH, Cho SG (2010) Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers 2(2):859–884. doi:10.3390/cancers2020859

    Article  PubMed Central  PubMed  Google Scholar 

  4. Shmelkov SV, St Clair R, Lyden D, Rafii S (2005) AC133/CD133/Prominin-1. Int J Biochem Cell Biol 37(4):715–719. doi:10.1016/j.biocel.2004.08.010

    Article  CAS  PubMed  Google Scholar 

  5. Mimeault M, Hauke R, Mehta PP, Batra SK (2007) Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med 11(5):981–1011. doi:10.1111/j.1582-4934.2007.00088.x

    Article  CAS  PubMed  Google Scholar 

  6. Kai K, Arima Y, Kamiya T, Saya H (2010) Breast cancer stem cells. Breast Cancer 17(2):80–85. doi:10.1007/s12282-009-0176-y

    Article  PubMed  Google Scholar 

  7. Zhang M, Rosen JM (2006) Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev 16(1):60–64. doi:10.1016/j.gde.2005.12.008

    Article  PubMed  Google Scholar 

  8. Gerber JM, Qin L, Kowalski J et al (2011) Characterization of chronic myeloid leukemia stem cells. Am J Hematol 86(1):31–37. doi:10.1002/ajh.21915

    Article  PubMed Central  PubMed  Google Scholar 

  9. Fleischman AG (2012) ALDH marks leukemia stem cell. Blood 119(15):3376–3377. doi:10.1182/blood-2012-02-406751

    Article  CAS  PubMed  Google Scholar 

  10. Schimmer AD, O’Brien S, Kantarjian H et al (2008) A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 14(24):8295–8301. doi:10.1158/1078-0432.CCR-08-0999

    Article  CAS  PubMed  Google Scholar 

  11. Brenner C, Kroemer G (2000) Mitochondria: the death signal integrators. Science 289(5482):1150–1151

    Article  CAS  PubMed  Google Scholar 

  12. Gogvadze V, Orrenius S, Zhivotovsky B (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18(4):165–173. doi:10.1016/j.tcb.2008.01.006

    Article  CAS  PubMed  Google Scholar 

  13. Modica-Napolitano JS, Singh KK (2004) Mitochondrial dysfunction in cancer. Mitochondrion 4(5–6):755–762. doi:10.1016/j.mito.2004.07.027

    Article  CAS  PubMed  Google Scholar 

  14. Ye XQ, Li Q, Wang GH et al (2011) Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer Journal international du cancer 129(4):820–831. doi:10.1002/ijc.25944

    Article  CAS  Google Scholar 

  15. Diehn M, Cho RW, Lobo NA et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783. doi:10.1038/nature07733

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Lonergan T, Bavister B, Brenner C (2007) Mitochondria in stem cells. Mitochondrion 7(5):289–296. doi:10.1016/j.mito.2007.05.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Lonergan T, Brenner C, Bavister B (2006) Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Physiol 208(1):149–153. doi:10.1002/jcp.20641

    Article  CAS  PubMed  Google Scholar 

  18. Bonnet S, Archer SL, Allalunis-Turner J et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51. doi:10.1016/j.ccr.2006.10.020

    Article  CAS  PubMed  Google Scholar 

  19. Chen LB (1988) Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4:155–181. doi:10.1146/annurev.cb.04.110188.001103

    Article  CAS  PubMed  Google Scholar 

  20. Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482. doi:10.1016/j.ccr.2008.05.005

    Article  CAS  PubMed  Google Scholar 

  21. Hockenbery DM (2002) A mitochondrial Achilles’ heel in cancer? Cancer Cell 2(1):1–2

    Article  CAS  PubMed  Google Scholar 

  22. Yu M, Shi Y, Wei X et al (2007) Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells. Toxicol Lett 170(1):83–93. doi:10.1016/j.toxlet.2007.02.013

    Article  CAS  PubMed  Google Scholar 

  23. Schieke SM, Ma M, Cao L et al (2008) Mitochondrial metabolism modulates differentiation and teratoma formation capacity in mouse embryonic stem cells. J Biol Chem 283(42):28506–28512. doi:10.1074/jbc.M802763200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Heerdt BG, Houston MA, Wilson AJ, Augenlicht LH (2003) The intrinsic mitochondrial membrane potential (Deltapsim) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis. Cancer Res 63(19):6311–6319

    CAS  PubMed  Google Scholar 

  25. Ho MM, Ng AV, Lam S, Hung JY (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67(10):4827–4833. doi:10.1158/0008-5472.CAN-06-3557

    Article  CAS  PubMed  Google Scholar 

  26. Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH (2007) Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 67(8):3716–3724. doi:10.1158/0008-5472.CAN-06-4343

    Article  CAS  PubMed  Google Scholar 

  27. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 65(14):6207–6219. doi:10.1158/0008-5472.CAN-05-0592

    Article  CAS  PubMed  Google Scholar 

  28. Hirschmann-Jax C, Foster AE, Wulf GG et al (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101(39):14228–14233. doi:10.1073/pnas.0400067101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Derdak Z, Fulop P, Sabo E et al (2006) Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 27(5):956–961. doi:10.1093/carcin/bgi335

    Article  CAS  PubMed  Google Scholar 

  30. Pecqueur C, Bui T, Gelly C et al (2008) Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization. FASEB Journal 22(1):9–18. doi:10.1096/fj.07-8945com

    Article  CAS  PubMed  Google Scholar 

  31. Wasilewski M, Scorrano L (2009) The changing shape of mitochondrial apoptosis. Trends Endocrinol Metab TEM 20(6):287–294. doi:10.1016/j.tem.2009.03.007

    Article  CAS  Google Scholar 

  32. Pietila M, Lehtonen S, Narhi M et al (2010) Mitochondrial function determines the viability and osteogenic potency of human mesenchymal stem cells. Tissue Eng Part C Methods 16(3):435–445. doi:10.1089/ten.tec.2009.0247

    Article  PubMed  Google Scholar 

  33. Yajima T, Ochiai H, Uchiyama T, Takano N, Shibahara T, Azuma T (2009) Resistance to cytotoxic chemotherapy-induced apoptosis in side population cells of human oral squamous cell carcinoma cell line Ho-1-N-1. Int J Oncol 35(2):273–280

    CAS  PubMed  Google Scholar 

  34. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160(2):189–200. doi:10.1083/jcb.200211046

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Levraut J, Iwase H, Shao ZH, Vanden Hoek TL, Schumacker PT (2003) Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation. Am J Physiol Heart Circ Physiol 284(2):H549–H558. doi:10.1152/ajpheart.00708.2002

    Article  CAS  PubMed  Google Scholar 

  36. Klein BY, Gal I, Libergal M, Ben-Bassat H (1996) Opposing effects on mitochondrial membrane potential by malonate and levamisole, whose effect on cell-mediated mineralization is antagonistic. J Cell Biochem 60(1):139–147. doi:10.1002/(SICI)1097-4644(19960101)60:1<139:AID-JCB16>3.0.CO;2-K

    Article  CAS  PubMed  Google Scholar 

  37. Shi X, Zhang Y, Zheng J, Pan J (2012) Reactive oxygen species in cancer stem cells. Antioxid Redox Signal 16(11):1215–1228. doi:10.1089/ars.2012.4529

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51(3):794–798

    CAS  PubMed  Google Scholar 

  39. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591. doi:10.1038/nrd2803

    Article  CAS  PubMed  Google Scholar 

  40. Liu L, Chen R, Huang S et al (2011) Knockdown of SOD1 sensitizes the CD34+ CML cells to imatinib therapy. Med Oncol 28(3):835–839. doi:10.1007/s12032-010-9529-9

    Article  CAS  PubMed  Google Scholar 

  41. Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF (2010) Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci USA 107(8):3722–3727. doi:10.1073/pnas.0915135107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Kim YS, Kang MJ, Cho YM (2013) Low production of reactive oxygen species and high DNA repair: mechanism of radioresistance of prostate cancer stem cells. Anticancer Res 33(10):4469–4474

    CAS  PubMed  Google Scholar 

  43. Kong Q, Lillehei KO (1998) Antioxidant inhibitors for cancer therapy. Med Hypotheses 51(5):405–409

    Article  CAS  PubMed  Google Scholar 

  44. Guzman ML, Li X, Corbett CA et al (2007) Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 110(13):4436–4444. doi:10.1182/blood-2007-05-088815

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Guzman ML, Rossi RM, Karnischky L et al (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105(11):4163–4169. doi:10.1182/blood-2004-10-4135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Jin Y, Lu Z, Ding K et al (2010) Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res 70(6):2516–2527. doi:10.1158/0008-5472.CAN-09-3950

    Article  CAS  PubMed  Google Scholar 

  47. Yahata T, Muguruma Y, Yumino S et al (2008) Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis. Stem Cells 26(12):3228–3236. doi:10.1634/stemcells.2008-0552

    Article  PubMed  Google Scholar 

  48. Ito K, Bernardi R, Morotti A et al (2008) PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453(7198):1072–1078. doi:10.1038/nature07016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Abdel-Wahab O, Levine RL (2010) Metabolism and the leukemic stem cell. J Exp Med 207(4):677–680. doi:10.1084/jem.20100523

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Biasutto L, Dong LF, Zoratti M, Neuzil J (2010) Mitochondrially targeted anti-cancer agents. Mitochondrion 10(6):670–681. doi:10.1016/j.mito.2010.06.004

    Article  CAS  PubMed  Google Scholar 

  51. Smith RA, Hartley RC, Murphy MP (2011) Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal 15(12):3021–3038. doi:10.1089/ars.2011.3969

    Article  CAS  PubMed  Google Scholar 

  52. Modica-Napolitano JS, Aprille JR (1987) Basis for the selective cytotoxicity of rhodamine 123. Cancer Res 47(16):4361–4365

    CAS  PubMed  Google Scholar 

  53. Modica-Napolitano JS, Nalbandian R, Kidd ME, Nalbandian A, Nguyen CC (2003) The selective in vitro cytotoxicity of carcinoma cells by AZT is enhanced by concurrent treatment with delocalized lipophilic cations. Cancer Lett 198(1):59–68

    Article  CAS  PubMed  Google Scholar 

  54. Fantin VR, Berardi MJ, Scorrano L, Korsmeyer SJ, Leder P (2002) A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2(1):29–42

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have no conflict of interests to declare.

Author information

Authors and Affiliations

  1. Graduate School of Medicine, Mie University, Tsu, Mie, Japan

    Bei-bei Zhang

  2. Department of Gastroenterology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, People’s Republic of China

    Dao-gang Wang

  3. Department of Clinical Laboratory, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China

    Fen-fen Guo

  4. Department of Clinical Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China

    Chao Xuan

Authors
  1. Bei-bei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dao-gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fen-fen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dao-gang Wang.

Additional information

Bei-bei Zhang and Dao-gang Wang have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Bb., Wang, Dg., Guo, Ff. et al. Mitochondrial membrane potential and reactive oxygen species in cancer stem cells. Familial Cancer 14, 19–23 (2015). https://doi.org/10.1007/s10689-014-9757-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-014-9757-9

Keywords

Search

Navigation