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Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift.

ABSTRACT: The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. Here, we demonstrate that hypoxia augments the capacity of melanoma cells to withstand cisplatin and doxorubicin cytotoxicity. We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate human-relevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin. The differences are manifested in magnitude of proliferative arrest and cell death rates, extent of mtDNA depletion, and impairment of mitochondrial respiration. In both models, cytotoxicity is mitigated by hypoxia, which augments glycolytic metabolism. Collectively, the findings implicate metabolic reprogramming in drug evasion and suggest that melanoma tumors with distinct genetic makeup may have differential drug vulnerabilities, highlighting the importance of precision anticancer treatments.

SUBMITTER: Zhuo M

PROVIDER: S-EPMC7193165 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift.

Zhuo Ming M Gorgun Falih M FM Tyler Douglas S DS Englander Ella W EW

FEBS open bio 20200414 5

The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. Here, we demonstrate that hypoxia augments the capacity of melanoma cells to withstand cisplatin and doxorubicin cytotoxicity. We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate human-relevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin. The differences are manifested in magnitude of ...[more]

PMID: 32134564

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Project description:Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use.

Project description:Objective: Athletes increasingly engage in repeated sprint training that consists of repeated short all-out effort interspersed by short periods of recovery. When performed in hypoxia (RSH), it may lead to greater training effects than in normoxia (RSN), however the underlying molecular mechanisms remain unclear. This study aimed at elucidating the effects of RSH on skeletal muscle oxidative and glycolytic adaptations as compared to RSN. Methods: Healthy young men performed nine repeated sprint training sessions in three weeks. Each training session consisted in six series of six sprints in either normoxia (FiO2 = 20.9%, RSN, n = 7) or normobaric hypoxia (FiO2 = 13.6%, RSH, n = 9). Before and after the training period, exercise performance was assessed by using repeated sprint ability (RSA) and Wingate tests. Vastus lateralis muscle biopsies were performed to investigate muscle metabolic adaptations using proteomic combined to western blotting analyses. Results: We observed similar improvements in RSA and Wingate tests in both RSH and RSN groups. Proteomic analysis revealed a decrease in several proteins involved in oxidative phosphorylation (OXPHOS) in both groups and this was confirmed with western blot showing significant reductions in complexes I and V protein levels. RSN and RSH increased protein levels of the glycolytic enzyme hexokinase II, while only RSH induced a significant increase in the glucose transporter 4 (GLUT4) protein levels, suggesting superior glycolytic adaptations in response to hypoxia. This phenotype is further supported by proteomics data showing significant increase of proteins involved in glycolysis. Our proteomics data showed in the RSH group a specific increase in several S100A family proteins, among which S100A13 was the most modified, a result confirmed by western blot. S100A proteins have recently been shown to accelerate glycolytic phenotype of cancer cells by activating the protein kinase B (Akt) pathway. Our data corroborate these findings by showing in RSH group increased Akt phosphorylation as well as increased levels of proteins related to Akt downstream effects such as enhanced translation. Conclusions: Altogether our data indicate that RSH, as compared to RSN, potentiates the muscle glycolytic phenotype, possibly through the activation of S100A13 and the Akt pathway.

Dataset Information

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift.

Publications

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift.

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