Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugs

Abstract

The majority of cancer cells harbor homoplasmic somatic mutations in the mitochondrial genome. We show here that mutations in mitochondrial DNA (mtDNA) are responsible for anticancer drug tolerance. We constructed several trans-mitochondrial hybrids (cybrids) with mtDNA derived from human pancreas cancer cell lines CFPAC-1 and CAPAN-2 as well as from healthy individuals. These cybrids contained the different mitochondrial genomes with the common nuclear background. We compared the mutant and wildtype cybrids for resistance against an apoptosis-inducing reagent and anticancer drugs by exposing the cybrids to staurosporine, 5-fluorouracil, and cisplatin in vitro, and found that all mutant cybrids were more resistant to the apoptosis-inducing and anticancer drugs than wild-type cybrids. Next, we transplanted mutant and wildtype cybrids into nude mice to generate tumors. Tumors derived from mutant cybrids were more resistant than those from wild-type cybrids in suppressing tumor growth and inducing massive apoptosis when 5-fluorouracil and cisplatin were administered. To confirm the tolerance of mutant cybrids to anticancer drugs, we transplanted a mixture of mutant and wild-type cybrids at a 1:1 ratio into nude mice and examined the effect by the drugs on the drift of the ratio of mutant and wild-type mtDNA. The mutant mtDNA showed better survival, indicating that mutant cybrids were more resistant to the anticancer drugs. Thus, we propose that mutations in the mitochondrial genome are potential targets for prognosis in the administration of anticancer drugs to cancer patients. (Cancer Sci 2009; 100: 1680-1687)

The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

“…Similarly, Lee et al (141) found that when evaluating TRAIL-induced apoptosis in SKHep1 hepatoma cells, Ú -cells were more resistant than parental cells to the effects of this cytokine; a different model (HeLa cells treated with photodynamic therapy or adriamycin) also showed resistance to apoptosis in Ú -cells (142). However, these data were in contrast to the observations by Mizutani et al (143), which revealed that cybrids derived from mitochondria were more resistant to CDDP than Ú -cells, an observation which agrees with previously cited results, as well as with data from Mizumachi et al (144) who reported that anthracycline-resistant head and neck cancer cells had a significantly higher mtDNA content. Furthermore, in alternative model systems, photodynamic approaches have revealed increases in cell death with mtDNA depletion (145,146); indeed, in L1210 murine leukemia cells, there was a significant increase in the sensitivity to mitochondriallyrelated photodamage in Ú -cells, a process giving rise to apoptotic death; when made resistant to ddC, CEM lymphoblast cells showed increases in their mtDNA content and expression (126).…”

Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

“…6 In colon cancer, mutations and microsatellite instability (MSI) of the mtDNA have been found in 8%-70% of the investigated cohorts. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Furthermore, mtDNA alterations have been proven as prognostic marker, 6 indicator of resistance to FU-based 6,24 and cisplatin chemotherapy, 24 and characteristic of cancer cells, which can be targeted by next-generation metal-based therapy as the recently published organometallic "half sandwich" compound [Os(η(6)-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6. 25 The future potential combined diagnostic function of mtDNA alterations to identify tumor cells, which are resistant to conventional cytotoxic drugs and/or responsive to new therapeutic approaches, requires to elucidate its association with other therapeutic markers, which, for example, are related to proliferation, apoptosis, and the EGFR pathway, and to define preanalytic conditions for reliable diagnostic routine.…”

Mitochondrial Genome Instability in Cancer

“…The interference of mt-mutations with anticancer therapies [Ohta, 2006;Mizutani et al, 2009] and the use of body fluids (sputum in lung and head-and-neck cancers, or urine in renal and urine-bladder malignancies) for the analysis of mt-mutations from tumor patients avoiding invasive techniques [Jakupciak et al, 2008] are 2 promising fields that remain to be further investigated.…”