Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

Abstract

Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells towards mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer.

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

“…In this regard, although the lack of induced apoptosis in the A2780 cell line after treatment with cisplatin doses as high as IC 90 had been previously reported, 17 controversial data may be found in the literature. 46,47 On the other hand, the lack of differences in cisplatin adducts between AT-0 and AT-1 times not only for the A2780 cells but also for the A549 and A2780cis cells (all repair active cells), demonstrated that there is an equilibrium between adducts being repaired/removed and new adducts being formed by the remaining intracellular cisplatin, at least in the 1 h time lapse studied, as suggested before. 48 Besides, the repair/removal of cisplatininduced DNA adducts in these cells seemed to be a relatively slow process, as described for A2780 23 and the other cells; 8,23,49 however, it is important to address that no adducts were detected 24 h after the end of treatment (data not shown).…”

Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab

“…Many molecularly targeted anti-cancer drugs that have been approved or are in development, including inhibitors of EGFR, PI3K, and mTOR and even some chemotherapeutic agents, like cisplatin [39], downregulate HIF-1α directly or indirectly [9,40,41], which can lead to activation of AMPK. Thus, co-targeting ACC, which we found is a rational therapeutic strategy for treatment of cetuximab-resistant HNSCC, could also improve the outcomes of other therapies targeting the Warburg effect.…”

ASCT2 (SLC1A5) is an EGFR-associated protein that can be co-targeted by cetuximab to sensitize cancer cells to ROS-induced apoptosis

“…It has been well documented that both ionizing radiation and cisplatin can induce a high level of ROS, which contribute to the antitumor activity of these therapies [37,38]. It will be interesting, therefore, to determine whether the therapeutic benefits observed in patients treated with the combination of cetuximab with radiation or cisplatin are achieved, in whole or in part, via a mechanism similar to the one we observed with cetuximab plus DCA, i.e., cetuximab downregulates ASCT2 in tumors, thereby sensitizing cancer cells to radiation- or cisplatin-induced ROS.…”