Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells

Abstract

Patients with high-grade serous ovarian cancer (HGSC) frequently receive platinum-based chemotherapeutics, such as cisplatin. Cisplatin binds to DNA and induces DNA-damage culminating in mitochondria-mediated apoptosis. Interestingly, mitochondrial DNA is critically affected by cisplatin but its relevance in cell death induction is scarcely investigated. We find that cisplatin sensitive HGSC cell lines contain higher mitochondrial content and higher levels of mitochondrial ROS (mtROS) than cells resistant to cisplatin induced cell death. In clonal sub-lines from OVCAR-3 mitochondrial content and basal oxygen consumption rate correlate with sensitivity to cisplatin induced apoptosis. Mitochondria are in two ways pivotal for cisplatin sensitivity because not only knock-down of BAX and BAK but also the ROS scavenger glutathione diminish cisplatin induced apoptosis. Mitochondrial ROS correlates with mitochondrial content and reduction of mitochondrial biogenesis by knock-down of transcription factors PGC1α or TFAM attenuates both mtROS induction and cisplatin induced apoptosis. Increasing mitochondrial ROS by inhibition or knock-down of the ROS-protective uncoupling protein UCP2 enhances cisplatin induced apoptosis. Similarly, enhancing ROS by high-dose ascorbic acid or H2O2 augments cisplatin induced apoptosis. In summary, mitochondrial content and the resulting mitochondrial capacity to produce ROS critically determine HGSC cell sensitivity to cisplatin induced apoptosis. In line with this observation, data from the human protein atlas (www.proteinatlas.org) indicates that high expression of mitochondrial marker proteins (TFAM and TIMM23) is a favorable prognostic factor in ovarian cancer patients. Thus, we propose mitochondrial content as a biomarker for the response to platinum-based therapies. Functionally, this might be exploited by increasing mitochondrial content or mitochondrial ROS production to enhance sensitivity to cisplatin based anti-cancer therapies.

Peer Review #1 of "Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups (v0.2)"

“…8A). This suggests that the cisplatin is not lowering the mitochondrial membrane potential, which agrees with Kleih and colleagues who observed that ovarian cancer cells treated with cisplatin also maintained their mitochondrial membrane potential (Cocetta et al 2019;Kleih et al 2019). Similarly, English et.…”

Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

“…The co-administration of MDR1 inhibitors with PARPi is a strategy that has not yet been explored in clinical trials [75], but future research may focus on targeting patients with ABCB1 mutations involved in PARPi resistance. Alteration in intracellular proteins that are able to bind and sequester platinum (including metallothioneins and glutathione [76,77]), and altered expression of pro-survival or anti-survival proteins have also been described as resistance mechanisms which reduce cellular availability of drugs. Proteomic analysis of paired primary and recurrent OC cells from ascites has revealed that RELA and STAT5 proteins cooperate in inducing the anti-apoptotic Bcl-X promoter activity and synergistically enhance Bcl-xL expression in chemo-resistant ovarian cancer cells [78].…”

Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

“…ROS is an active form of oxygen, and its induced cytotoxicity is an important mechanism for cisplatin to kill tumor cells [13]. Cisplatin induces high ROS levels that cause cancer cell apoptosis [14].…”