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.
Highlights
The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments
We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate humanrelevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin
While it is difficult to predict how genetic makeup might shape the melanoma cell phenotype, here, we show that B16F10 and YUMM1.7 cells have distinctive properties, markedly differing in cell morphology, glycolytic gene expression profiles, Abbreviations 2DG, 2-deoxy-D-glucose; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; mtDNA, mitochondrial DNA; Tfam, mitochondrial transcription factor A; NER, nucleotide excision repair; Oxygen consumption rates (OCR), oxygen consumption rates; SRC, spare respiratory capacity; Top2, topoisomerase 2
Summary
The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. 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. We studied responses of two mouse melanoma cell models to the widely used chemotherapeutic drugs, cisplatin and doxorubicin, which block cancer cell proliferation via induction of different types of DNA damage. While it is difficult to predict how genetic makeup might shape the melanoma cell phenotype, here, we show that B16F10 and YUMM1.7 cells have distinctive properties, markedly differing in cell morphology, glycolytic gene expression profiles, Abbreviations 2DG, 2-deoxy-D-glucose; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; mtDNA, mitochondrial DNA; Tfam, mitochondrial transcription factor A; NER, nucleotide excision repair; OCR, oxygen consumption rates; SRC, spare respiratory capacity; Top, topoisomerase 2. Our findings alert to the individual differences among tumors derived from the same type of tissue and to the critical importance of informed precisely tailored design of chemotherapeutic treatments in achieving desired outcomes
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