Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

We found that cisplatin resistant high-grade serous ovarian cancer cells lines were more oxidative than their sensitive counterpart, and that inhibition of oxidative phosphorylation restored cisplatin sensitivity

Rosario Avolio; Danilo Swann Matassa; Daniela Criscuolo; Matteo Landriscina; Franca Esposito

2020

Scholarcy highlights

  • Drug resistance is the major cause of cancer recurrence and metastasis, and involves different molecular mechanisms/targets affecting the events that are essential to ensure cell survival
  • The reduction of TKT is responsible for a switch from glycolysis to oxidative phosphorylation. Consistent with these results, combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhance cell death in triple-negative breast cancer cells. In line with these studies, and consistent with what was anticipated in a previous section in this review, we contributed to shedding further light on the correlation between drug resistance and cancer metabolic remodeling through the characterization in several cancer types of the molecular chaperone tumor necrosis factor receptor associated protein 1, which has been extensively described for its role in the stress adaptive response of cancer cells, and has recently emerged as a critical regulator of cancer cell metabolism and chemoresistance
  • We focused on different metabolic signatures in the context of cancer chemoresistance, paying special attention to the role of TRAP1 chaperone in cancer metabolic regulation
  • Today, increasing evidence suggests the need of extensive reprogramming of mitochondrial activity in the development of cancer drug resistance
  • This review, besides summarizing how metabolism, oxidative stress adaptation, and chemoresistance are strictly interconnected, shows how TRAP1 stays at the crossroads of these processes, shedding new light on the molecular networks which form the bases of several cancers
  • The apparent contradictions that still make TRAP1 an attractive cancer biomarker will be unveiled after deep analyses of the TRAP1 pathway in individual cancer types and upon careful characterization of unique/selective TRAP1 client proteins in the regulation of cancer cell metabolism and drug resistance

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