Role of mitochondria in carcinogenesis

• Authors: Paulina Tokarz , Janusz Blasiak
• Languages of publication: EN

Abstracts

EN

Mitochondria play the central role in supplying cells with ATP and are also the major source of reactive oxygen species (ROS) - molecules of both regulatory and destructive nature. Dysfunction of mitochondrial metabolism and/or morphology have been frequently reported in human cancers. This dysfunction can be associated with mitochondrial DNA (mtDNA) damage, which may be changed into mutations in mtDNA coding sequences, or the displacement-loop region, changes in the mtDNA copy number or mtDNA microsatellite instability. All these features are frequently associated with human cancers. Mutations in mtDNA can disturb the functioning of the ROS-producing organelle and further affect the entire cell which may contribute to genomic instability typical for cancer cells. Although the association between some mtDNA mutations and cancer is well established, the causative relationship between these two features is largely unknown. A hint suggesting the driving role of mtDNA mutations in carcinogenesis comes from the observation of tumor promotion after mtDNA depletion. Mitochondria with damaged DNA may alter signaling of the mitochondrial apoptosis pathway promoting cancer cell survival and conferring resistance to anticancer drugs. This resistance may be underlined by mtDNA copy number depletion. Therefore, mitochondria are considered a promising target in anticancer therapy and several mitochondria-targeting drugs are in preclinical and clinical trials. Some other aspects of mitochondrial structure and functions, including morphology and redox potential, can also be associated with cancer transformation and constitute new anticancer targets. Recently, several studies have disclosed new mechanisms underlying the association between mitochondria and cancer, including the protection of mtDNA by telomerase, suggesting new approaches in mitochondria-oriented anti-cancer therapy.

Keywords

EN

cancer; mitochondria; mtDNA; ROS; anti-cancer therapy

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2014
• Volume: 61
• Issue: 4
• Pages: 671-678

Dates

published

2014

received

2014-06-22

revised

2014-09-17

accepted

2014-11-03

(unknown)

2014-12-11

Contributors

author

Paulina Tokarz

• Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland

author

Janusz Blasiak

• Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland

References

• Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, Birch-Machin MA, von Zglinicki T, Saretzki G (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 121: 1046-1053.
• Arismendi-Morillo G (2009) Electron microscopy morphology of the mitochondrial network in human cancer. Int J Biochem Cell Biol 41: 2062-2068.
• Bagchi D, McGinn TR, Ye X, Bagchi M, Krohn RL, Chatterjee A, Stohs SJ (2002) Helicobacter pylori-induced oxidative stress and DNA damage in a primary culture of human gastric mucosal cells. Dig Dis Sci 47: 1405-1412.
• Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38: 515-517.
• Biswas G, Anandatheerthavarada HK, Avadhani NG (2005) Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes. Cell Death Differ 12: 266-278.
• De Paepe B (2012) Mitochondrial markers for cancer: relevance to diagnosis, therapy, and prognosis and general understanding of malignant disease mechanisms. International Scholarly Research Network 2012: article ID 217162.
• Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S (1994) Decline with age of the respiratory chain activity in human skeletal muscle. Biochim Biophys Acta 1226: 73-82.
• Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138: 2073-2087.
• Cao Z, Song JH, Kang YW, Yoon JH, Nam SW, Lee JY, Park WS (2010) Analysis of succinate dehydrogenase subunit B gene alterations in gastric cancers. Pathol Int 60: 559-565.
• Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2: 324-329.
• Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18: 6927-6933.
• de Grey AD (1997) A proposed refinement of the mitochondrial free radical theory of aging. Bioessays 19: 161-166.
• de Souza-Pinto NC, Mason PA, Hashiguchi K, Weissman L, Tian J, Guay D, Lebel M, Stevnsner TV, Rasmussen LJ, Bohr VA (2009) Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst) 8: 704-719.
• DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11-20.
• Delsite RL, Rasmussen LJ, Rasmussen AK, Kalen A, Goswami PC, Singh KK (2003) Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus. Mutagenesis 18: 497-503.
• Elson JL, Samuels DC, Turnbull DM, Chinnery PF (2001) Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am J Hum Genet 68: 802-806.
• Ericson NG, Kulawiec M, Vermulst M, Sheahan K, O'Sullivan J, Salk JJ, Bielas JH (2012) Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet 8: e1002689.
• Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9: 425-434.
• Fath MA, Diers AR, Aykin-Burns N, Simons AL, Hua L, Spitz DR (2009) Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells. Cancer Biol Ther 8: 1228-1236.
• Fayet G, Jansson M, Sternberg D, Moslemi AR, Blondy P, Lombes A, Fardeau M, Oldfors A (2002) Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul Disord 12: 484-493.
• Ferraresi R, Troiano L, Pinti M, Roat E, Lugli E, Quaglino D, Taverna D, Bellizzi D, Passarino G, Cossarizza A (2008) Resistance of mtDNA-depleted cells to apoptosis. Cytometry A 73: 528-537.
• Fliss MM, Usadel H, Caballero OL, Wu L, Buta MR, Ele. SM, Jen J, Sidransky D (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287: 2017-2019.
• Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29: 909-916.
• Griguer CE, Oliva CR, Gillespie GY (2005) Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. J Neurooncol 74: 123-133.
• Grollman AP, Moriya M (1993) Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet 9: 246-249.
• Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 29: 929-935.
• Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM (2008) Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res 68: 2321-2328.
• Hattori K, Tanaka M, Sugiyama S, Obayashi T, Ito T, Satake T, Hanaki Y, Asai J, Nagano M, Ozawa T (1991) Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am Heart J 121: 1735-1742.
• Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8: 311-321.
• Heerdt BG, Houston MA, Augenlicht LH (2005) The intrinsic mitochondrial membrane potential of colonic carcinoma cells is linked to the probability of tumor progression. Cancer Res 65: 9861-9867.
• Herbener GH (1976) A morphometric study of age-dependent changes in mitochondrial population of mouse liver and heart. J Gerontol 31: 8-12.
• Houston MA, Augenlicht LH, Heerdt BG (2011) Stable differences in intrinsic mitochondrial membrane potential of tumor cell subpopulations reflect phenotypic heterogeneity. Int J Cell Biol 2011: 978583.
• Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134: 703-707.
• Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H, Johnson S, Ivanova E, Kost-Alimova M, Protopopov A, Wang YA, Shirihai OS, Chin L, DePinho RA (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148: 651-663.
• Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320: 661-664.
• Jakob S, Haendeler J (2007) Molecular mechanisms involved in endothelial cell aging: role of telomerase reverse transcriptase. Z Gerontol Geriatr 40: 334-338.
• Jose C, Bellance N, Rossignol R (2010) Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim Biophys Acta 1807: 552- 561.
• Kluza J, Jendoubi M, Ballot C, Dammak A, Jonneaux A, Idziorek T, Joha S, Dauphin V, Malet-Martino M, Balayssac S, Maboudou P, Briand G, Formstecher P, Quesnel B, Marchetti P (2011) Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells. PLoS One 6: e21924.
• Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10: 375-388.
• Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11: 325-337.
• Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M, Blasiak J, Skorski T (2006) BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108: 319-327.
• Koshikawa N, Hayashi J, Nakagawara A, Takenaga K (2009) Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J Biol Chem 284: 33185-33194.
• Krokan HE, Standal R, Slupphaug G (1997) DNA glycosylases in the base excision repair of DNA. Biochem J 325: 1-16.
• Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481-484.
• Kulawiec M, Arnouk H, Desouki MM, Kazim L, Still I, Singh KK (2006) Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer. Cancer Biol Ther 5: 967-975.
• Kulawiec M, Owens KM, Singh KK (2009) Cancer cell mitochondria confer apoptosis resistance and promote metastasis. Cancer Biol Ther 8: 1378-1385.
• Lapointe J, Hekimi S (2010) When a theory of aging ages badly. Cell Mol Life Sci 67: 1-8.
• Larman TC, DePalma SR, Hadjipanayis AG; Cancer Genome Atlas Research Network, Protopopov A, Zhang J, Gabriel SB, Chin L, Seidman CE, Kucherlapati R, Seidman JG (2012) Spectrum of somatic mitochondrial mutations in five cancers. Proc Natl Acad Sci USA 109: 14087-14091.
• Lee HC, Li SH, Lin JC, Wu CC, Yeh DC, Wei YH (2004) Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma. Mutat Res 547: 71-78.
• Lee HC, Wei YH (2005) Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 37: 822-834.
• Lee HC, Wei YH (2009) Mitochondrial DNA instability and metabolic shift in human cancers. Int J Mol Sci 10: 674-701.
• Li LZ (2012) Imaging mitochondrial redox potential and its possible link to tumor metastatic potential. J Bioenerg Biomembr 44: 645-653.
• Lim HY, Ho QS, Low J, Choolani M, Wong KP (2011) Respiratory competent mitochondria in human ovarian and peritoneal cancer. Mitochondrion 11: 437-443.
• Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1: 642-645.
• Lipetz J, Cristofalo VJ (1972) Ultrastructural changes accompanying the aging of human diploid cells in culture. J Ultrastruct Res 39: 43-56.
• Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B (2009) An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15: 3172-3176.
• Lu J, Sharma LK, Bai Y (2009) Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res 19: 802-815.
• Maher JC, Wangpaichitr M, Savaraj N, Kurtoglu M, Lampidis TJ (2007) Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol Cancer Ther 6: 732-741.
• Mason KD, Khaw SL, Rayeroux KC, Chew E, Lee EF, Fairlie WD, Grigg AP, Seymour JF, Szer J, Huang DC, Roberts AW (2009) The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 23: 2034-2041.
• Mason KD, Vandenberg CJ, Scott CL, Wei AH, Cory S, Huang DC, Roberts AW (2008) In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas. Proc Natl Acad Sci USA 105: 17961-17966.
• Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC, Bohr VA (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30: 2-10.
• Melov S, Schneider JA, Coskun PE, Bennett DA, Wallace DC (1999) Mitochondrial DNA rearrangements in aging human brain and in situ PCR of mtDNA. Neurobiol Aging 20: 565-571.
• Meyer JN, Boyd WA, Azzam GA, Haugen AC, Freedman JH, Van Houten B (2007) Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans. Genome Biol 8: R70.
• Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286: 774-779.
• Miller KW, Dawson JL, Hagelberg E (1996) A concordance of nucleotide substitutions in the first and second hypervariable segments of the human mtDNA control region. Int J Legal Med 109: 107-113.
• National Institutes of Health (2013) Available at
• O'Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, Viallet J, Cheson BD (2009) Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 113: 299-305.
• Ozawa T (1995) Mechanism of somatic mitochondrial DNA mutations associated with age and diseases. Biochim Biophys Acta 1271: 177-189.
• Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W, Keating MJ, Huang P (2003) Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 278: 37832-37839.
• Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25: 4633-4646.
• Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) MtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102: 719-724.
• Pfeiffer T, Schuster S, Bonhoeffer S (2001) Cooperation and competition in the evolution of ATP-producing pathways. Science 292: 504-507.
• Ricketts CJ, Shuch B, Vocke CD, Metwalli AR, Bratslavsky G, Middelton L, Yang Y, Wei MH, Pautler SE, Peterson J, Stolle CA, Zbar B, Merino MJ, Schmidt LS, Pinto PA, Srinivasan R, Pacak K, Linehan WM (2012) Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol 188: 2063-7113.
• Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18: 3163-3169.
• Salomon AR, Voehringer DW, Herzenberg LA, Khosla C (2000) Understanding and exploiting the mechanistic basis for selectivity of polyketide inhibitors of F(0)F(1)-ATPase. Proc Natl Acad Sci USA 97: 14766-14771.
• Scott DA, Richardson AD, Filipp FV, Knutzen CA, Chiang GG, Ronai ZA, Osterman AL, Smith JW (2011) Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem 286: 42626-42634.
• Shidara Y, Yamagata K, Kanamori T, akano K, Kwong JQ, Manfredi G, Oda H, Ohta S (2005) Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res 65: 1655-1663.
• Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 102: 5618-5623.
• Singh KK, Ayyasamy V, Owens KM, Koul MS, Vujcic M (2009) Mutations in mitochondrial DNA polymerase-gamma promote breast tumorigenesis. J Hum Genet 54: 516-524.
• Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui SI (2005) Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene 354: 140-146.
• Slupianek A, Falinski R, Znojek P, Stoklosa T, Flis S, Doneddu V, Pytel D, Synowiec E, Blasiak J, Bellacosa A, Skorski T (2013) BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. Leukemia 27: 629-634.
• Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK (2008) A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 7: 1182-1190.
• Taanman JW (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410: 103-123.
• Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood TB, Turnbull DM (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Invest 112: 1351-1360.
• Tebbs RS, Flannery ML, Meneses JJ, Hartmann A, Tucker JD, Thompson LH, Cleaver JE, Pedersen RA (1999) Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev Biol 208: 513-529.
• Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417-423.
• Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324: 1029-1033.
• Vives-Bauza C, Gonzalo R, Manfredi G, Garcia-Arumi E, Andreu AL (2006) Enhanced ROS production and antioxidant defenses in cybrids harbouring mutations in mtDNA. Neurosci Lett 391: 136-141.
• Wallace DC (1992) Diseases of the mitochondrial DNA. Annu Rev Biochem 61: 1175-1212.
• Wallace DC (1994) Mitochondrial DNA mutations in diseases of energy metabolism. J Bioenerg Biomembr 26: 241-250.
• Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12: 685-698.
• Wang D, Kreutzer DA, Essigmann JM (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res 400: 99-115.
• Wang X, Moraes CT (2011) Increases in mitochondrial biogenesis impair carcinogenesis at multiple levels. Mol Oncol 5: 399-409.
• Wang Y, Liu VW, Tsang PC, Chiu PM, Cheung AN, Khoo US, Nagley P, Ngan HY (2006) Microsatellite instability in mitochondrial genome of common female cancers. Int J Gynecol Cancer 16: Suppl 1: 259-266.
• Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107: 8788-8793.
• Wilson PD, Franks LM (1975) The effect of age on mitochondrial ultrastructure and enzymes. Adv Exp Med Biol 53: 171-183.
• Xie CH, Naito A, Mizumachi T, Evans TT, Douglas MG, Cooney CA, Fan CY, Higuchi M (2007) Mitochondrial regulation of cancer associated nuclear DNA methylation. Biochem Biophys Res Commun 364: 656-661.
• Yu M (2011) Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci 89: 65-71.
• Zhang H, Trachootham D, Lu W, Carew J, Giles FJ, Keating MJ, Arlinghaus RB, Huang P (2008) Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia 22: 1191-1199.