Abstract
Introduction
Radiotherapy is a mainstay of cancer treatment. Clinical studies revealed a heterogenous response to radiotherapy, from a complete response to even disease progression. To that end, finding the relative prognostic factors of disease outcomes and predictive factors of treatment efficacy and toxicity is essential. It has been demonstrated that radiation response depends on DNA damage response, cell cycle phase, oxygen concentration, and growth rate. Emerging evidence suggests that altered mitochondrial metabolism is associated with radioresistance.
Methods
This article provides a comprehensive evaluation of the role of mitochondria in radiotherapy efficacy and toxicity. In addition, it demonstrates how mitochondria might be involved in the famous 6Rs of radiobiology.
Results
In terms of this idea, decreasing the mitochondrial metabolism of cancer cells may increase radiation response, and enhancing the mitochondrial metabolism of normal cells may reduce radiation toxicity. Enhancing the normal cells (including immune cells) mitochondrial metabolism can potentially improve the tumor response by enhancing immune reactivation. Future studies are invited to examine the impacts of mitochondrial metabolism on radiation efficacy and toxicity.
Graphical abstract
Improving radiotherapy response with diminishing cancer cells’ mitochondrial metabolism, and reducing radiotherapy toxicity with enhancing normal cells’ mitochondrial metabolism.
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References
Abdelkarem OAI, Choudhury A, Burnet NG, Summersgill HR, West CML (2022) Effect of race and ethnicity on risk of radiotherapy toxicity and implications for radiogenomics. Clin Oncol 34(10):653–669. https://doi.org/10.1016/j.clon.2022.03.013
Ahmed KM, Zhang H, Park CC (2013) NF-κB regulates radioresistance mediated By β1-integrin in three-dimensional culture of breast cancer cells. Can Res 73(12):3737–3748. https://doi.org/10.1158/0008-5472.Can-12-3537
Akbari H, Taghizadeh-Hesary F, Heike Y, Bahadori M (2019) Cell energy: a new hypothesis in decoding cancer evolution. Arch Iran Med 22(12):733–735
Akbari H, Taghizadeh-Hesary F, Bahadori M (2022) Mitochondria determine response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy: An evidence-based hypothesis. Mitochondrion 62:151–158. https://doi.org/10.1016/j.mito.2021.12.001
Albensi BC (2019) What is nuclear factor kappa B (NF-κB) doing in and to the mitochondrion? Review. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2019.00154
Al-Qadami G, Van Sebille Y, Le H, Bowen J (2019) Gut microbiota: implications for radiotherapy response and radiotherapy-induced mucositis. Expert Rev Gastroenterol Hepatol 13(5):485–496. https://doi.org/10.1080/17474124.2019.1595586
Anzic M, Marinko T (2020) Effect of adjuvant hormonal therapy on the development of pulmonary fibrosis after postoperative radiotherapy for breast cancer. J Breast Cancer 23(5):449–459
Arbini AA, Guerra F, Greco M et al (2013) Mitochondrial DNA depletion sensitizes cancer cells to PARP inhibitors by translational and post-translational repression of BRCA2. Oncogenesis 2(12):e82. https://doi.org/10.1038/oncsis.2013.45
Argiris A, Miao J, Cristea MC et al (2021) A dose-finding study followed by a phase II randomized, placebo-controlled trial of chemoradiotherapy with or without veliparib in stage III non-small-cell lung cancer: SWOG 1206(8811). Clin Lung Cancer 22(4):313-323.e1. https://doi.org/10.1016/j.cllc.2021.02.009
Arnold CR, Mangesius J, Skvortsova I-I, Ganswindt U (2020) The role of cancer stem cells in radiation resistance. Review Front Oncol. https://doi.org/10.3389/fonc.2020.00164
Atlante A, Calissano P, Bobba A, Azzariti A, Marra E, Passarella S (2000) Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death. J Biol Chem 275(47):37159–37166. https://doi.org/10.1074/jbc.M002361200
Babaei G, Aziz SG-G, Jaghi NZZ (2021) EMT, cancer stem cells and autophagy; the three main axes of metastasis. Biomed Pharmacother 133:110909. https://doi.org/10.1016/j.biopha.2020.110909
Banerjee Mustafi S, Aznar N, Dwivedi SK et al (2016) Mitochondrial BMI1 maintains bioenergetic homeostasis in cells. Faseb j 30(12):4042–4055. https://doi.org/10.1096/fj.201600321R
Barcellini A, Loap P, Murata K et al (2021) PARP inhibitors in combination with radiotherapy: to do or not to do? Cancers. https://doi.org/10.3390/cancers13215380
Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74(3):665–674. https://doi.org/10.1158/0008-5472.Can-13-0992
Belgioia L, Morbelli SD, Corvò R (2020) Prediction of response in head and neck tumor: focus on main hot topics in research. Front Oncol 10:604965. https://doi.org/10.3389/fonc.2020.604965
Benej M, Hong X, Vibhute S et al (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115(42):10756–10761. https://doi.org/10.1073/pnas.1808945115
Bentle MS, Reinicke KE, Bey EA, Spitz DR, Boothman DA (2006) Calcium-dependent modulation of poly(ADP-ribose) polymerase-1 alters cellular metabolism and DNA repair*. J Biol Chem 281(44):33684–33696. https://doi.org/10.1074/jbc.M603678200
Bergman M, Fountoukidis G, Smith D, Ahlgren J, Lambe M, Valachis A (2022) Effect of smoking on treatment efficacy and toxicity in patients with cancer: a systematic review and meta-analysis. Cancers 14(17):4117
Bonanno JA, Shyam R, Choi M, Ogando DG (2022) The H(+) transporter SLC4A11: roles in metabolism oxidative stress and mitochondrial uncoupling. Cells. https://doi.org/10.3390/cells11020197
Bonora M, Pinton P (2014) The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Review. Front Oncol. https://doi.org/10.3389/fonc.2014.00302
Bossi P, Platini F (2017) Radiotherapy plus EGFR inhibitors: synergistic modalities. Cancers Head Neck. 2(1):2. https://doi.org/10.1186/s41199-016-0020-y
Bouitbir J, Panajatovic MV, Frechard T, Roos NJ, Krähenbühl S (2020) Imatinib and dasatinib provoke mitochondrial dysfunction leading to oxidative stress in C2C12 myotubes and human RD cells. Front Pharmacol 11:1106. https://doi.org/10.3389/fphar.2020.01106
Boustani J, Grapin M, Laurent PA, Apetoh L, Mirjolet C (2019) The 6th R of radiobiology: reactivation of anti-tumor immune response. Cancers. https://doi.org/10.3390/cancers11060860
Byun HK, Han MC, Yang K et al (2021) Physical and biological characteristics of particle therapy for oncologists. Cancer Res Treat 53(3):611–620. https://doi.org/10.4143/crt.2021.066
Carpenter EL, Chagani S, Nelson D et al (2019) Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAF(V600E) mutation bearing metastatic melanoma cells. Mol Carcinog 58(9):1680–1690. https://doi.org/10.1002/mc.23068
Carvalho HA, Villar RC (2018) Radiotherapy and immune response: the systemic effects of a local treatment. Clinics 73(suppl 1):e557s. https://doi.org/10.6061/clinics/2018/e557s
Chamoto K, Chowdhury PS, Kumar A et al (2017) Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A 114(5):E761-e770. https://doi.org/10.1073/pnas.1620433114
Chandel NS (2010) Mitochondrial complex III: an essential component of universal oxygen sensing machinery? Respir Physiol Neurobiol 174(3):175–181. https://doi.org/10.1016/j.resp.2010.08.004
Chang L, Graham PH, Hao J et al (2014) PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis 5(10):e1437. https://doi.org/10.1038/cddis.2014.415
Cheng J, Moore S, Gomez-Galeno J, Lee DH, Okolotowicz KJ, Cashman JR (2019) A novel small molecule inhibits tumor growth and synergizes effects of enzalutamide on prostate cancer. J Pharmacol Exp Ther 371(3):703–712. https://doi.org/10.1124/jpet.119.261040
Chew MT, Jones B, Hill M, Bradley DA (2021) Radiation, a two-edged sword: from untoward effects to fractionated radiotherapy. Radiat Phys Chem 178:108994. https://doi.org/10.1016/j.radphyschem.2020.108994
Choudhury FK (2021) Mitochondrial redox metabolism: the epicenter of metabolism during cancer progression. Antioxidants. https://doi.org/10.3390/antiox10111838
Chu C, Niu X, Ou X, Hu C (2019) LAPTM4B knockdown increases the radiosensitivity of EGFR-overexpressing radioresistant nasopharyngeal cancer cells by inhibiting autophagy. Onco Targets Ther 12:5661–5677. https://doi.org/10.2147/ott.S207810
Cocetta V, Ragazzi E, Montopoli M (2019) Mitochondrial involvement in cisplatin resistance. Int J Mol Sci. https://doi.org/10.3390/ijms20143384
Consiglio CR, Udartseva O, Ramsey KD, Bush C, Gollnick SO (2020) Enzalutamide, an androgen receptor antagonist, enhances myeloid cell-mediated immune suppression and tumor progression. Cancer Immunol Res 8(9):1215–1227. https://doi.org/10.1158/2326-6066.Cir-19-0371
Cruz-Gregorio A, Aranda-Rivera AK, Pedraza-Chaverri J (2020) Human papillomavirus-related cancers and mitochondria. Virus Res 286:198016. https://doi.org/10.1016/j.virusres.2020.198016
Cuyàs E, Fernández-Arroyo S, Verdura S, Lupu R, Joven J, Menendez JA (2022) Metabolomic and mitochondrial fingerprinting of the epithelial-to-mesenchymal transition (EMT) in non-tumorigenic and tumorigenic human breast cells. Cancers. https://doi.org/10.3390/cancers14246214
Dai S, Zhou Z, Chen Z, Xu G, Chen Y (2019) Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors. Cells. https://doi.org/10.3390/cells8060614
Dai N, Groenendyk J, Michalak M (2021) Binding proteins | Ca2+ binding/buffering proteins: ER luminal proteins☆. In: Jez J (ed) Encyclopedia of Biological Chemistry III (Third Edition). Elsevier, New York, pp 534–546
Daniel Y, Lelou E, Aninat C, Corlu A, Cabillic F (2021) Interplay between metabolism reprogramming and epithelial-to-mesenchymal transition in cancer stem cells. Cancers 13(8):1973
De Courcy L, Bezak E, Marcu LG (2020) Gender-dependent radiotherapy: the next step in personalised medicine? Crit Rev Oncol Hematol 147:102881. https://doi.org/10.1016/j.critrevonc.2020.102881
de la Cruz López KG, Toledo Guzmán ME, Sánchez EO, García CA (2019) mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer review. Front Oncol. https://doi.org/10.3389/fonc.2019.01373
de Mello AH, Costa AB, Engel JDG, Rezin GT (2018) Mitochondrial dysfunction in obesity. Life Sci 192:26–32. https://doi.org/10.1016/j.lfs.2017.11.019
Delaney G, Jacob S, Featherstone C, Barton M (2005) The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 104(6):1129–1137. https://doi.org/10.1002/cncr.21324
Delgado-Deida Y, Alula KM, Theiss AL (2020) The influence of mitochondrial-directed regulation of Wnt signaling on tumorigenesis. Gastroenterol Rep 8(3):215–223. https://doi.org/10.1093/gastro/goaa025
den Besten G, Gerding A, van Dijk TH et al (2015) Protection against the metabolic syndrome by guar gum-derived short-chain fatty acids depends on peroxisome proliferator-activated receptor γ and glucagon-like peptide-1. PLoS ONE 10(8):e0136364. https://doi.org/10.1371/journal.pone.0136364
Deng X, Wang Q, Cheng M et al (2020) Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer. J Cancer 11(4):962–973. https://doi.org/10.7150/jca.34330
Desdín-Micó G, Soto-Heredero G, Mittelbrunn M (2018) Mitochondrial activity in T cells. Mitochondrion 41:51–57. https://doi.org/10.1016/j.mito.2017.10.006
Dewson G (2001) Bax to the wall: Bax-and Bak-induced mitochondrial dysfunction in apoptosis. Trends Biochem Sci 26(6):353
Dok R, Kalev P, Van Limbergen EJ et al (2014) p16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer Res 74(6):1739–1751. https://doi.org/10.1158/0008-5472.Can-13-2479
Dörr W (2015) Radiobiology of tissue reactions. Ann ICRP 44(1 Suppl):58–68. https://doi.org/10.1177/0146645314560686
Drobin K, Marczyk M, Halle M et al (2020) Molecular profiling for predictors of radiosensitivity in patients with breast or head-and-neck cancer. Cancers. https://doi.org/10.3390/cancers12030753
Duberley KE, Heales SJ, Abramov AY et al (2014) Effect of Coenzyme Q10 supplementation on mitochondrial electron transport chain activity and mitochondrial oxidative stress in Coenzyme Q10 deficient human neuronal cells. Int J Biochem Cell Biol 50:60–63. https://doi.org/10.1016/j.biocel.2014.02.003
Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS (2007) Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. J Clin Invest 117(9):2723–2734. https://doi.org/10.1172/jci31604
Ellenberger T, Tomkinson AE (2008) Eukaryotic DNA ligases: structural and functional insights. Annu Rev Biochem 77:313–338. https://doi.org/10.1146/annurev.biochem.77.061306.123941
Ericson NG, Kulawiec M, Vermulst M et al (2012) Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet 8(6):e1002689. https://doi.org/10.1371/journal.pgen.1002689
Facchino S, Abdouh M, Chatoo W, Bernier G (2010) BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30(30):10096–10111. https://doi.org/10.1523/jneurosci.1634-10.2010
Fan F, Zhuang J, Zhou P, Liu X, Luo Y (2017) MicroRNA-34a promotes mitochondrial dysfunction-induced apoptosis in human lens epithelial cells by targeting Notch2. Oncotarget 8(66):110209–110220. https://doi.org/10.18632/oncotarget.22597
Fazilaty H, Behnam B (2014) The perivascular niche governs an autoregulatory network to support breast cancer metastasis. Cell Biol Int 38(6):691–694. https://doi.org/10.1002/cbin.10261
Fazilaty H, Gardaneh M, Bahrami T, Salmaninejad A, Behnam B (2013) Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumour Biol 34(4):2019–2030. https://doi.org/10.1007/s13277-013-0831-y
Fazilaty H, Gardaneh M, Akbari P, Zekri A, Behnam B (2016) SLUG and SOX9 cooperatively regulate tumor initiating niche factors in breast cancer. Cancer Microenviron 9(1):71–74. https://doi.org/10.1007/s12307-015-0176-8
Feng LR, Wolff BS, Liwang J et al (2020) Cancer-related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction. Int J Mol Med 45(2):485–496. https://doi.org/10.3892/ijmm.2019.4435
Fessler E, Eckl EM, Schmitt S et al (2020) A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579(7799):433–437. https://doi.org/10.1038/s41586-020-2076-4
Gallyas F Jr, Sumegi B (2020) Mitochondrial Protection by PARP Inhibition. Int J Mol Sci. https://doi.org/10.3390/ijms21082767
Gangopadhyay NN, Luketich JD, Opest A et al (2011) Inhibition of poly(ADP-ribose) polymerase (PARP) induces apoptosis in lung cancer cell lines. Cancer Invest 29(9):608–616. https://doi.org/10.3109/07357907.2011.621916
Gao M, Wang J, Wang W, Liu J, Wong CW (2011) Phosphatidylinositol 3-kinase affects mitochondrial function in part through inducing peroxisome proliferator-activated receptor γ coactivator-1β expression. Br J Pharmacol 162(4):1000–1008. https://doi.org/10.1111/j.1476-5381.2010.01105.x
Ghashghaei M, Niazi TM, Heravi M et al (2018) Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen-sensitive prostate cancer cells. Prostate 78(1):64–75. https://doi.org/10.1002/pros.23445
Ghosh P, Vidal C, Dey S, Zhang L (2020) Mitochondria targeting as an effective strategy for cancer therapy. Int J Mol Sci 21(9):3363
Golden EB, Formenti SC, Schiff PB (2014) Taxanes as radiosensitizers. Anticancer Drugs 25(5):502–511. https://doi.org/10.1097/cad.0000000000000055
Guarda V, Schroeder L, Pawlita M et al (2022) Prevalence of transcriptionally active HPV infection in tumor-free oropharyngeal tissue of OPSCC-patients original research. Front Oncol. https://doi.org/10.3389/fonc.2022.835814
Guillot C, Favaudon V, Herceg Z et al (2014) PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitrohepatocellular carcinoma models. BMC Cancer 14(1):603. https://doi.org/10.1186/1471-2407-14-603
Hashimoto T, Urushihara Y, Murata Y, Fujishima Y, Hosoi Y (2022) AMPK increases expression of ATM through transcriptional factor Sp1 and induces radioresistance under severe hypoxia in glioblastoma cell lines. Biochem Biophys Res Commun 590:82–88. https://doi.org/10.1016/j.bbrc.2021.12.076
He K, Zhang S, Pang J et al (2021) Genomic profiling reveals novel predictive biomarkers for chemo-radiotherapy toxicity and efficacy in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 111(3):e437
Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H (2017) Mechanistic investigations of the mitochondrial complex i inhibitor rotenone in the context of pharmacological and safety evaluation. Sci Rep 7:45465. https://doi.org/10.1038/srep45465
Henke N, Albrecht P, Pfeiffer A, Toutzaris D, Zanger K, Methner A (2012) Stromal interaction molecule 1 (STIM1) is involved in the regulation of mitochondrial shape and bioenergetics and plays a role in oxidative stress. J Biol Chem 287(50):42042–42052. https://doi.org/10.1074/jbc.M112.417212
Hernández L, Terradas M, Camps J, Martín M, Tusell L, Genescà A (2015) Aging and radiation: bad companions. Aging Cell 14(2):153–161. https://doi.org/10.1111/acel.12306
Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19(2):121–135. https://doi.org/10.1038/nrm.2017.95
Hidalgo-Gutiérrez A, González-García P, Díaz-Casado ME et al (2021) Metabolic targets of coenzyme Q10 in mitochondria. Antioxidants. https://doi.org/10.3390/antiox10040520
Hitosugi T, Fan J, Chung T-W et al (2011) Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 44(6):864–877. https://doi.org/10.1016/j.molcel.2011.10.015
Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122(7):2049–2063. https://doi.org/10.1053/gast.2002.33613
Holley AK, Miao L, St Clair DK, St Clair WH (2014) Redox-modulated phenomena and radiation therapy: the central role of superoxide dismutases. Antioxid Redox Signal 20(10):1567–1589. https://doi.org/10.1089/ars.2012.5000
Hornhardt S, Rößler U, Sauter W et al (2014) Genetic factors in individual radiation sensitivity. DNA Repair 16:54–65. https://doi.org/10.1016/j.dnarep.2014.02.001
Houshyari M, Taghizadeh-Hesary F (2022) Is mitochondrial metabolism a new predictive biomarker for antiprogrammed cell death protein-1 immunotherapy? JCO Oncol Pract. https://doi.org/10.1200/OP.22.00733
Hu JW, Sun P, Zhang DX, Xiong WJ, Mi J (2014) Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts. Cell Signal 26(10):2210–2216. https://doi.org/10.1016/j.cellsig.2014.04.015
Huang R, Zhou P-K (2020) HIF-1 signaling: a key orchestrator of cancer radioresistance. Radiat Med Protect. 1(1):7–14. https://doi.org/10.1016/j.radmp.2020.01.006
Imdad S, Lim W, Kim JH, Kang C (2022) Intertwined relationship of mitochondrial metabolism, gut microbiome and exercise potential. Int J Mol Sci. https://doi.org/10.3390/ijms23052679
Itoh K, Ye P, Matsumiya T, Tanji K, Ozaki T (2015) Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria. J Clin Biochem Nutr 56(2):91–97. https://doi.org/10.3164/jcbn.14-134
Ju H-Q, Lin J-F, Tian T, Xie D, Xu R-H (2020) NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Sig Transduct Targeted Ther. 5(1):231. https://doi.org/10.1038/s41392-020-00326-0
Kaina B, Beltzig L, Strik H (2022) Temozolomide—just a radiosensitizer? Perspective. Front Oncol. https://doi.org/10.3389/fonc.2022.912821
Kamp WM, Wang PY, Hwang PM (2016) TP53 mutation, mitochondria and cancer. Curr Opin Genet Dev 38:16–22. https://doi.org/10.1016/j.gde.2016.02.007
Ki Y, Kim W, Kim YH et al (2017) Effect of coenzyme Q10 on radiation nephropathy in rats. J Korean Med Sci 32(5):757–763. https://doi.org/10.3346/jkms.2017.32.5.757
Kim MS, Kim W, Park IH et al (2015) Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery. Radiat Oncol J 33(4):265–275. https://doi.org/10.3857/roj.2015.33.4.265
Kim J, Yang G, Kim Y, Kim J, Ha J (2016) AMPK activators: mechanisms of action and physiological activities. Exp Mol Med 48(4):e224–e224. https://doi.org/10.1038/emm.2016.16
Kim W, Lee S, Seo D et al (2019) Cellular stress responses in radiotherapy. Cells. https://doi.org/10.3390/cells8091105
Kong L, Zhou X, Wu Y et al (2015) Targeting HOTAIR induces mitochondria related apoptosis and inhibits tumor growth in head and neck squamous cell carcinoma in vitro and in vivo. Curr Mol Med 15(10):952–960
Kong X, Yu D, Wang Z, Li S (2021) Relationship between p53 status and the bioeffect of ionizing radiation. Oncol Lett 22(3):661. https://doi.org/10.3892/ol.2021.12922
Kozlov S, Gueven N, Keating K, Ramsay J, Lavin MF (2003) ATP activates ataxia-telangiectasia mutated (ATM) in vitro Importance of Autophosphorylation. J Biol Chem 278(11):9309–9317. https://doi.org/10.1074/jbc.m300003200
Kumari R, Jat P (2021) Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Review. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2021.645593
Kung-Chun Chiu D, Pui-Wah Tse A, Law C-T et al (2019) Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway. Cell Death Dis 10(12):934. https://doi.org/10.1038/s41419-019-2155-3
Laurini E, Marson D, Fermeglia A, Aulic S, Fermeglia M, Pricl S (2020) Role of Rad51 and DNA repair in cancer: a molecular perspective. Pharmacol Ther 208:107492. https://doi.org/10.1016/j.pharmthera.2020.107492
Lawler JM, Demaree SR (2001) Relationship between NADP-specific isocitrate dehydrogenase and glutathione peroxidase in aging rat skeletal muscle. Mech Ageing Dev 122(3):291–304. https://doi.org/10.1016/s0047-6374(00)00235-9
Leal-Esteban LC, Fajas L (2020) Cell cycle regulators in cancer cell metabolism. Biochim Biophys Acta Mol Basis Dis 1866(5):165715. https://doi.org/10.1016/j.bbadis.2020.165715
Lechner M, Liu J, Masterson L, Fenton TR (2022) HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clinl Oncol. 19(5):306–327. https://doi.org/10.1038/s41571-022-00603-7
Lee JH, Paull TT (2020) Mitochondria at the crossroads of ATM-mediated stress signaling and regulation of reactive oxygen species. Redox Biol 32:101511. https://doi.org/10.1016/j.redox.2020.101511
Lee JH, Choi SI, Kim RK, Cho EW, Kim IG (2018) Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. Sci Rep 8(1):10711. https://doi.org/10.1038/s41598-018-29142-x
Lee H, Park J, Jung K, Lim J, Hong S (2022) HS-173, a novel PI3K inhibitor enhances radiosensitivity of breast cancer cells. Int J Radiat Res 20(2):347–352
Lei X, Lin H, Wang J et al (2022) Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression. Nat Commun 13(1):3882. https://doi.org/10.1038/s41467-022-31417-x
Lévy N, Martz A, Bresson A, Spenlehauer C, de Murcia G, Ménissier-de MJ (2006) XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage. Nucleic Acids Res 34(1):32–41. https://doi.org/10.1093/nar/gkj409
Li S, Chou AP, Chen W et al (2013) Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol 15(1):57–68. https://doi.org/10.1093/neuonc/nos261
Li S, Sun C, Gu Y et al (2019) Mutation of IDH1 aggravates the fatty acid-induced oxidative stress in HCT116 cells by affecting the mitochondrial respiratory chain. Mol Med Rep 19(4):2509–2518. https://doi.org/10.3892/mmr.2019.9903
Li J, Li Y, Chen L et al (2020) p53/PGC-1α-mediated mitochondrial dysfunction promotes PC3 prostate cancer cell apoptosis. Mol Med Rep 22(1):155–164. https://doi.org/10.3892/mmr.2020.11121
Li Z, Zhang Y, Hong W et al (2022) Gut microbiota modulate radiotherapy-associated antitumor immune responses against hepatocellular carcinoma Via STING signaling. Gut Microb. 14(1):2119055. https://doi.org/10.1080/19490976.2022.2119055
Liang H, Deng L, Hou Y et al (2017) Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 8(1):1736. https://doi.org/10.1038/s41467-017-01566-5
Lima TI, Guimarães D, Oliveira AG et al (2019) Opposing action of NCoR1 and PGC-1α in mitochondrial redox homeostasis. Free Radic Biol Med 143:203–208. https://doi.org/10.1016/j.freeradbiomed.2019.08.006
Lin YL, Sengupta S, Gurdziel K, Bell GW, Jacks T, Flores ER (2009) p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genet 5(10):e1000680. https://doi.org/10.1371/journal.pgen.1000680
Liu X, Shan G (2021) Mitochondria encoded non-coding RNAs in cell physiology. Review. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2021.713729
Liu Y, Shi Y (2020) Mitochondria as a target in cancer treatment. MedComm. 1(2):129–139. https://doi.org/10.1002/mco2.16
Liu R, Fan M, Candas D et al (2015) CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance. Mol Cancer Ther 14(9):2090–2102. https://doi.org/10.1158/1535-7163.Mct-15-0017
Liu C, Mann D, Sinha UK, Kokot NC (2018) The molecular mechanisms of increased radiosensitivity of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC): an extensive review. J Otolaryngol Head Neck Surg 47(1):59. https://doi.org/10.1186/s40463-018-0302-y
Liu YP, Zheng CC, Huang YN, He ML, Xu WW, Li B (2020) Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm 2(3):315–340. https://doi.org/10.1002/mco2.55
Lomeli N, Di K, Pearre DC, Chung T-F, Bota DA (2020) Mitochondrial-associated impairments of temozolomide on neural stem/progenitor cells and hippocampal neurons. Mitochondrion 52:56–66. https://doi.org/10.1016/j.mito.2020.02.001
Loubiere C, Clavel S, Gilleron J et al (2017) The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells. Sci Rep 7(1):5040. https://doi.org/10.1038/s41598-017-05052-2
Lu JP, Monardo L, Bryskin I et al (2010) Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase. Prostate Cancer Prostatic Dis 13(1):39–46. https://doi.org/10.1038/pcan.2009.24
Lu H, Li X, Luo Z, Liu J, Fan Z (2013) Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A. Mol Cancer Ther 12(10):2187–2199. https://doi.org/10.1158/1535-7163.Mct-12-1245
Luoma RL, Butler MW, Stahlschmidt ZR (2016) Plasticity of immunity in response to eating. J Exp Biol 219(Pt 13):1965–1968. https://doi.org/10.1242/jeb.138123
Lynam-Lennon N, Maher SG, Maguire A et al (2014) Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma. PLoS ONE 9(6):e100738. https://doi.org/10.1371/journal.pone.0100738
Ma J, Lu Y, Zhang S et al (2018) β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer. Cell Death Differ 25(8):1473–1485. https://doi.org/10.1038/s41418-017-0055-6
Ma K, Chen G, Li W, Kepp O, Zhu Y, Chen Q (2020) Mitophagy, Mitochondrial Homeostasis, and Cell Fate. Front Cell Dev Biol 8:467. https://doi.org/10.3389/fcell.2020.00467
Madani A, Alack K, Richter MJ, Krüger K (2018) Immune-regulating effects of exercise on cigarette smoke-induced inflammation. J Inflamm Res 11:155–167. https://doi.org/10.2147/jir.S141149
Malińska D, Więckowski MR, Michalska B et al (2019) Mitochondria as a possible target for nicotine action. J Bioenerg Biomembr 51(4):259–276. https://doi.org/10.1007/s10863-019-09800-z
Marcu LDL, Dasu A (2015) The Six Rs of head and neck cancer radiotherapy. In: Marcu L (ed) Contemporary issues in head and neck cancer management. InTechOpen, London
Mauro C, Leow SC, Anso E et al (2011) NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol 13(10):1272–1279. https://doi.org/10.1038/ncb2324
McCann E, O’Sullivan J, Marcone S (2021) Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response. Transl Oncol 14(1):100905. https://doi.org/10.1016/j.tranon.2020.100905
McGee SF, Mazzarello S, Caudrelier JM et al (2018) Optimal sequence of adjuvant endocrine and radiation therapy in early-stage breast cancer—a systematic review. Cancer Treat Rev 69:132–142. https://doi.org/10.1016/j.ctrv.2018.06.015
Meier JA, Larner AC (2014) Toward a new STATe: the role of STATs in mitochondrial function. Semin Immunol 26(1):20–28. https://doi.org/10.1016/j.smim.2013.12.005
Memme JM, Erlich AT, Phukan G, Hood DA (2021) Exercise and mitochondrial health. J Physiol 599(3):803–817. https://doi.org/10.1113/jp278853
Michmerhuizen AR, Lerner LM, Pesch AM et al (2022) Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models. Npj Breast Cancer. 8(1):31. https://doi.org/10.1038/s41523-022-00397-y
Mikuła-Pietrasik J, Witucka A, Pakuła M et al (2019) Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells. Cell Mol Life Sci 76(4):681–697. https://doi.org/10.1007/s00018-018-2954-1
Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D (2015) LAPTM4b recruits the LAT1–4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun 6(1):7250. https://doi.org/10.1038/ncomms8250
Mrozowski RM (2015) Targeting the Ser/Thr protein kinase RSK to reduce breast cancer metastasis. Vanderbilt University. https://ir.vanderbilt.edu/bitstream/handle/1803/13000/dissertationRMrozowski.pdf?sequence=1&isAllowed=y
Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F (2019) Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ 26(4):690–702. https://doi.org/10.1038/s41418-019-0292-y
Nicolatou-Galitis O, Bossi P, Orlandi E, René-Jean B (2021) The role of benzydamine in prevention and treatment of chemoradiotherapy-induced mucositis. Support Care Cancer 29(10):5701–5709. https://doi.org/10.1007/s00520-021-06048-5
Overgaard J, Aznar MC, Bacchus C et al (2022) Personalised radiation therapy taking both the tumour and patient into consideration. Radiother Oncol 166:A1-a5. https://doi.org/10.1016/j.radonc.2022.01.010
Pal S, Yadav P, Sainis KB, Shankar BS (2018) TNF-α and IGF-1 differentially modulate ionizing radiation responses of lung cancer cell lines. Cytokine 101:89–98. https://doi.org/10.1016/j.cyto.2016.06.015
Pan L, Zhou L, Yin W, Bai J, Liu R (2018) miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol 53(1):124–136. https://doi.org/10.3892/ijo.2018.4380
Parker DJ, Iyer A, Shah S et al (2015) A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation. J Cell Sci 128(22):4171–4182. https://doi.org/10.1242/jcs.172429
Pate KT, Stringari C, Sprowl-Tanio S et al (2014) Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. Embo j 33(13):1454–1473. https://doi.org/10.15252/embj.201488598
Paupe V, Prudent J (2018) New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochem Biophys Res Commun 500(1):75–86. https://doi.org/10.1016/j.bbrc.2017.05.039
Pedersen H, Anne Adanma Obara E, Elbæk KJ, Vitting-Serup K, Hamerlik P (2020) Replication protein A (RPA) mediates radio-resistance of glioblastoma cancer stem-like cells. Int J Mol Sci 21(5):1588
Peiris-Pagès M, Bonuccelli G, Sotgia F, Lisanti MP (2018) Mitochondrial fission as a driver of stemness in tumor cells: mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling. Oncotarget 9(17):13254–13275. https://doi.org/10.18632/oncotarget.24285
Porębska N, Latko M, Kucińska M, Zakrzewska M, Otlewski J, Opaliński Ł (2018) Targeting cellular trafficking of fibroblast growth factor receptors as a strategy for selective cancer treatment. J Clin Med. https://doi.org/10.3390/jcm8010007
Pour Khavari A, Liu Y, He E, Skog S, Haghdoost S (2018) Serum 8-Oxo-dG as a predictor of sensitivity and outcome of radiotherapy and chemotherapy of upper gastrointestinal tumours. Oxid Med Cell Longev 2018:4153574. https://doi.org/10.1155/2018/4153574
Pratson CL, Larkins MC, Karimian BH et al (2021) The impact of smoking, alcohol use, recurrent disease, and age on the development of neck fibrosis in head and neck cancer patients following radiation therapy. Front Oncol. https://doi.org/10.3389/fonc.2021.707418
Qiao B, Kerr M, Groselj B et al (2013) Imatinib radiosensitizes bladder cancer by targeting homologous recombination. Cancer Res 73(5):1611–1620. https://doi.org/10.1158/0008-5472.Can-12-1170
Rakotomalala A, Escande A, Furlan A, Meignan S, Lartigau E (2021) Hypoxia in solid tumors: how low oxygenation impacts the “Six Rs” of radiotherapy. Review. Front Endocrinol. https://doi.org/10.3389/fendo.2021.742215
Ribas V, García-Ruiz C, Fernández-Checa JC (2014) Glutathione and Mitochondria. Front Pharmacol 5:151. https://doi.org/10.3389/fphar.2014.00151
Rieckmann T, Tribius S, Grob TJ et al (2013) HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 107(2):242–246. https://doi.org/10.1016/j.radonc.2013.03.013
Rodrigues G, Sanatani M (2012) Age and comorbidity considerations related to radiotherapy and chemotherapy administration. Semin Radiat Oncol. 22(4):277–283. https://doi.org/10.1016/j.semradonc.2012.05.004
Rodrigues NR, Macedo GE, Martins IK et al (2018) Short-term sleep deprivation with exposure to nocturnal light alters mitochondrial bioenergetics in Drosophila. Free Radic Biol Med 120:395–406. https://doi.org/10.1016/j.freeradbiomed.2018.04.549
Rose M, Burgess JT, O’Byrne K, Richard DJ, Bolderson E (2020) PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Review. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2020.564601
Rühle A, Perez RL, Glowa C et al (2017) Cisplatin radiosensitizes radioresistant human mesenchymal stem cells. Oncotarget 8(50):87809–87820. https://doi.org/10.18632/oncotarget.21214
Rydström J (2006) Mitochondrial NADPH transhydrogenase and disease. Biochem Biophys Acta 1757(5):721–726. https://doi.org/10.1016/j.bbabio.2006.03.010
Saha T, Dash C, Jayabalan R et al (2022) Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat Nanotechnol 17(1):98–106. https://doi.org/10.1038/s41565-021-01000-4
Salazar-Roa M, Malumbres M (2017) Fueling the cell division cycle. Trends in Cell Biol 27(1):69–81. https://doi.org/10.1016/j.tcb.2016.08.009
Seiwert TY, Zuo Z, Keck MK et al (2015) Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 21(3):632–641. https://doi.org/10.1158/1078-0432.Ccr-13-3310
Shahrokni A, Wu AJ, Carter J, Lichtman SM (2016) Long-term toxicity of cancer treatment in older patients. Clin Geriatr Med 32(1):63–80. https://doi.org/10.1016/j.cger.2015.08.005
Shen H, Hau E, Joshi S, Dilda PJ, McDonald KL (2015) Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism. Mol Cancer Ther 14(8):1794–1804. https://doi.org/10.1158/1535-7163.Mct-15-0247
Shi Y, Lim SK, Liang Q et al (2019) Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 567(7748):341–346. https://doi.org/10.1038/s41586-019-0993-x
Shi Y, Wang Y, Jiang H et al (2021) Mitochondrial dysfunction induces radioresistance in colorectal cancer by activating [Ca(2+)](m)-PDP1-PDH-histone acetylation retrograde signaling. Cell Death Dis 12(9):837. https://doi.org/10.1038/s41419-021-03984-2
Shi X, Yang J, Deng S et al (2022) TGF-β signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol 15(1):135. https://doi.org/10.1186/s13045-022-01349-6
Shiau JP, Chuang YT, Cheng YB et al (2022) Impacts of oxidative Stress and PI3K/AKT/mTOR on metabolism and the future direction of investigating fucoidan-modulated metabolism. Antioxidants. https://doi.org/10.3390/antiox11050911
Shin MK, Cheong JH (2019) Mitochondria-centric bioenergetic characteristics in cancer stem-like cells. Arch Pharm Res 42(2):113–127. https://doi.org/10.1007/s12272-019-01127-y
Shinde A, Jung H, Lee H et al (2021) TNF-α differentially modulates subunit levels of respiratory electron transport complexes of ER/PR +ve/−ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential. Cancer Metab 9(1):19. https://doi.org/10.1186/s40170-021-00254-9
Singh DD, Parveen A, Yadav DK (2021) Role of PARP in TNBC: mechanism of inhibition, clinical applications, and resistance. Biomedicines 9(11):1512
Skvortsova I, Popper BA, Skvortsov S et al (2005) Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin’s lymphoma cells. J Radiat Res 46(2):241–248. https://doi.org/10.1269/jrr.46.241
Slone HB, Peters LJ, Milas L (1979) Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma2. J Natl Cancer Inst 63(5):1229–1235. https://doi.org/10.1093/jnci/63.5.1229
Song Y, Xiao H, Yang Z et al (2017) The predictive value of pre- and post-induction chemotherapy plasma EBV DNA level and tumor volume for the radiosensitivity of locally advanced nasopharyngeal carcinoma. Excli J 16:1268–1275. https://doi.org/10.17179/excli2017-752
Song S, Jiang Z, Spezia-Lindner DE et al (2020) BHRF1 enhances EBV mediated nasopharyngeal carcinoma tumorigenesis through modulating mitophagy associated with mitochondrial membrane permeabilization transition. Cells. https://doi.org/10.3390/cells9051158
Sprung CN, Forrester HB, Siva S, Martin OA (2015) Immunological markers that predict radiation toxicity. Cancer Lett 368(2):191–197. https://doi.org/10.1016/j.canlet.2015.01.045
Srinivas US, Dyczkowski J, Beißbarth T et al (2015) 5-Fluorouracil sensitizes colorectal tumor cells towards double stranded DNA breaks by interfering with homologous recombination repair. Oncotarget 6(14):12574–12586. https://doi.org/10.18632/oncotarget.3728
Srivastava S (2017) The mitochondrial basis of aging and age-related disorders. Genes. https://doi.org/10.3390/genes8120398
Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM (2015) Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol 141(11):1985–1994. https://doi.org/10.1007/s00432-015-1974-6
Stuani L, Sabatier M, Saland E et al (2021) Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J Exp Med. https://doi.org/10.1084/jem.20200924
Sultana R, Abdel-Fatah T, Perry C et al (2013) Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. PLoS ONE 8(2):e57098. https://doi.org/10.1371/journal.pone.0057098
Suwa T, Kobayashi M, Nam J-M, Harada H (2021) Tumor microenvironment and radioresistance. Exp Mol Med 53(6):1029–1035. https://doi.org/10.1038/s12276-021-00640-9
Syljuåsen RG (2019) Cell cycle effects in radiation oncology. In: Wenz F (ed) Radiation oncology. Springer International Publishing, Cham, pp 1–8
Taghizadeh-Hesary F, Akbari H, Bahadori M, Behnam B (2022) Targeted anti-mitochondrial therapy: the future of oncology. Genes 13(10):1728
Tang D, Kang R, Livesey KM et al (2011) High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab 13(6):701–711. https://doi.org/10.1016/j.cmet.2011.04.008
Tang H, Peng S, Dong Y et al (2019) MARCH5 overexpression contributes to tumor growth and metastasis and associates with poor survival in breast cancer. Cancer Manag Res 11:201–215. https://doi.org/10.2147/cmar.S190694
Tapodi A, Bognar Z, Szabo C, Gallyas F, Sumegi B, Hocsak E (2019) PARP inhibition induces Akt-mediated cytoprotective effects through the formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome. Biochem Pharmacol 162:98–108. https://doi.org/10.1016/j.bcp.2018.10.005
Tarrado-Castellarnau M, de Atauri P, Cascante M (2016) Oncogenic regulation of tumor metabolic reprogramming. Oncotarget 7(38):62726–62753. https://doi.org/10.18632/oncotarget.10911
Traish AM, Abdallah B, Yu G (2011) Androgen deficiency and mitochondrial dysfunction: implications for fatigue, muscle dysfunction, insulin resistance, diabetes, and cardiovascular disease. Horm Mol Biol Clin Investig 8(1):431–444. https://doi.org/10.1515/hmbci.2011.132
Tran AN, Lai A, Li S et al (2014) Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro Oncol 16(3):414–420. https://doi.org/10.1093/neuonc/not198
Trapani D, Franzoi MA, Burstein HJ et al (2022) Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification. Ann Oncol 33(7):702–712. https://doi.org/10.1016/j.annonc.2022.03.273
Unten Y, Murai M, Koshitaka T et al (2022) Comprehensive understanding of multiple actions of anticancer drug tamoxifen in isolated mitochondria. Biochem Biophys Acta 1863(2):148520. https://doi.org/10.1016/j.bbabio.2021.148520
Vaezi A, Feldman CH, Niedernhofer LJ (2011) ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer. Pharmgenomics Pers Med 4:47–63. https://doi.org/10.2147/pgpm.S20317
van Attikum H, Gasser SM (2005) ATP-dependent chromatin remodeling and DNA double-strand break repair. Cell Cycle 4(8):1011–1014. https://doi.org/10.4161/cc.4.8.1887
van Gisbergen MW, Offermans K, Voets AM et al (2020) Mitochondrial dysfunction inhibits hypoxia-induced HIF-1α stabilization and expression of its downstream targets. Front Oncol 10:770. https://doi.org/10.3389/fonc.2020.00770
Vatca M, Lucas JT Jr, Laudadio J et al (2014) Retrospective analysis of the impact of HPV status and smoking on mucositis in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemotherapy and radiotherapy. Oral Oncol 50(9):869–876. https://doi.org/10.1016/j.oraloncology.2014.06.010
Vaupel P, Multhoff G (2021) Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol 599(6):1745–1757. https://doi.org/10.1113/jp278810
Veuger SJ, Hunter JE, Durkacz BW (2009) Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. Oncogene 28(6):832–842. https://doi.org/10.1038/onc.2008.439
Viale A, Pettazzoni P, Lyssiotis CA et al (2014) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514(7524):628–632. https://doi.org/10.1038/nature13611
Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12(10):685–698. https://doi.org/10.1038/nrc3365
Wan YY, Zhang JF, Yang ZJ et al (2014) Involvement of Drp1 in hypoxia-induced migration of human glioblastoma U251 cells. Oncol Rep 32(2):619–626. https://doi.org/10.3892/or.2014.3235
Wang K, Tepper JE (2021) Radiation therapy-associated toxicity: etiology, management, and prevention. CA Cancer J Clin 71(5):437–454. https://doi.org/10.3322/caac.21689
Wang PY, Ma W, Park JY et al (2013) Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med 368(11):1027–1032. https://doi.org/10.1056/NEJMoa1214091
Wang N, Huang R, Yang K, He Y, Gao Y, Dong D (2022) Interfering with mitochondrial dynamics sensitizes glioblastoma multiforme to temozolomide chemotherapy. J Cell Mol Med 26(3):893–912. https://doi.org/10.1111/jcmm.17147
Weber R, Groth C, Lasser S et al (2021) IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cellular Immunol 359:104254. https://doi.org/10.1016/j.cellimm.2020.104254
Willenborg S, Sanin DE, Jais A et al (2021) Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab 33(12):2398-2414.e9. https://doi.org/10.1016/j.cmet.2021.10.004
Wu D, Sanin DE, Everts B et al (2016) Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44(6):1325–1336. https://doi.org/10.1016/j.immuni.2016.06.006
Wu K, Luan G, Xu Y et al (2020) Cigarette smoke extract increases mitochondrial membrane permeability through activation of adenine nucleotide translocator (ANT) in lung epithelial cells. Biochem Biophys Res Commun 525(3):733–739. https://doi.org/10.1016/j.bbrc.2020.02.160
Xie Y, Lv Y, Zhang Y, Liang Z, Han L, Xie Y (2019) LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering Mff-dependent mitochondrial fission and activating the JNK signaling pathway. Biomed Pharmacother 109:679–689. https://doi.org/10.1016/j.biopha.2018.10.097
Xu C, Xu J, Ji G et al (2019) Deficiency of X-ray repair cross-complementing group 1 in primordial germ cells contributes to male infertility. FASEB J 33(6):7427–7436
Xu D, Wu J, Dong L et al (2021) Serpinc1 acts as a tumor suppressor in hepatocellular carcinoma through inducing apoptosis and blocking macrophage polarization in an ubiquitin-proteasome manner. Front Oncol 11:738607. https://doi.org/10.3389/fonc.2021.738607
Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773. https://doi.org/10.1056/NEJMoa0808710
Yao W, Zhu S, Li P, Zhang S (2019) Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway. Cancer Cell Int 19(1):97. https://doi.org/10.1186/s12935-019-0812-3
Yashar CM (2018) 23—basic principles in gynecologic radiotherapy. In: DiSaia PJ, Creasman WT, Mannel RS, McMeekin DS, Mutch DG (eds) Clinical Gynecologic Oncology (Ninth Edition). Elsevier, New York, pp 586-605.e3
Yoon YS, Lee JH, Hwang SC, Choi KS, Yoon G (2005) TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells. Oncogene 24(11):1895–1903. https://doi.org/10.1038/sj.onc.1208262
Yu Y, Guan H, Jiang L, Li X, Xing L, Sun X (2020) Nimotuzumab, an EGFR-targeted antibody, promotes radiosensitivity of recurrent esophageal squamous cell carcinoma. Int J Oncol 56(4):945–956. https://doi.org/10.3892/ijo.2020.4981
Zeb A, Choubey V, Gupta R et al (2021) A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy. Redox Biol 48:102186. https://doi.org/10.1016/j.redox.2021.102186
Zhang S, Wang B, Xiao H et al (2020a) LncRNA HOTAIR enhances breast cancer radioresistance through facilitating HSPA1A expression via sequestering miR-449b-5p. Thoracic Cancer 11(7):1801–1816. https://doi.org/10.1111/1759-7714.13450
Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B (2020b) Mitochondrial Sirtuin 3: new emerging biological function and therapeutic target. Theranostics 10(18):8315–8342. https://doi.org/10.7150/thno.45922
Zhang W, Li L, Guo E et al (2022) Inhibition of PDK1 enhances radiosensitivity and reverses epithelial-mesenchymal transition in nasopharyngeal carcinoma. Head Neck 44(7):1576–1587. https://doi.org/10.1002/hed.27053
Zhao H, Jiang H, Li Z et al (2017) 2-Methoxyestradiol enhances radiosensitivity in radioresistant melanoma MDA-MB-435R cells by regulating glycolysis via HIF-1α/PDK1 axis. Int J Oncol 50(5):1531–1540. https://doi.org/10.3892/ijo.2017.3924
Zhao Y, Yi J, Tao L et al (2018) Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma. Cell Death Dis 9(4):433. https://doi.org/10.1038/s41419-018-0466-4
Zhao R, Feng T, Gao L et al (2022) PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2. J Exp Clin Cancer Res 41(1):125. https://doi.org/10.1186/s13046-022-02331-3
Zheng P, Xiong Q, Wu Y et al (2015) Quantitative proteomics analysis reveals novel insights into mechanisms of action of long noncoding RNA Hox transcript antisense intergenic RNA (HOTAIR) in HeLa cells. Mol Cell Proteom 14(6):1447–1463. https://doi.org/10.1074/mcp.M114.043984
Zheng H, Jarvis IWH, Bottai M, Dreij K, Stenius U (2018) TGF beta promotes repair of bulky DNA damage through increased ERCC1/XPF and ERCC1/XPA interaction. Carcinogenesis 40(4):580–591. https://doi.org/10.1093/carcin/bgy156
Zhou W, Sun M, Li GH et al (2013) Activation of the phosphorylation of ATM contributes to radioresistance of glioma stem cells. Oncol Rep 30(4):1793–1801. https://doi.org/10.3892/or.2013.2614
Zhou S, Zhang M, Zhou C, Wang W, Yang H, Ye W (2020) The role of epithelial-mesenchymal transition in regulating radioresistance. Crit Rev Oncol/hematol. 150:102961. https://doi.org/10.1016/j.critrevonc.2020.102961
Zou Y, Fang F, Ding YJ et al (2016) Notch 2 signaling contributes to cell growth, anti-apoptosis and metastasis in laryngeal squamous cell carcinoma. Mol Med Rep 14(4):3517–3524
Acknowledgements
We dedicate this article to the loving memory of our beloved mentor Moslem Bahadori, who was a pioneer in structuring the “National Council for Medical Education” and “National Organization for Educational Evaluation”, and a founder of the Iranian National Tuberculosis and Lung Diseases Research Center in Iran.
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Taghizadeh-Hesary, F., Houshyari, M. & Farhadi, M. Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity. J Cancer Res Clin Oncol 149, 6719–6741 (2023). https://doi.org/10.1007/s00432-023-04592-7
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DOI: https://doi.org/10.1007/s00432-023-04592-7