Abstract
PDH-driven metabolic reprogramming is necessary for BRAFV600E-induced senescence in melanoma.
Major finding: PDH-driven metabolic reprogramming is necessary for BRAFV600E-induced senescence in melanoma.
Mechanism: Deregulated expression of PDK1 and PDP2 triggers PDH dephosphorylation and activation during OIS.
Impact: PDK1 depletion promotes tumor regression and sensitizes melanoma cells to BRAF inhibitors.
Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism that limits malignant transformation in response to aberrant activation of oncogenes. Dysregulation of oncogenes also promotes metabolic reprogramming to support increased proliferation, but the role of metabolic signaling in the regulation of OIS is unknown. Kaplon and colleagues performed metabolic profiling of cells undergoing mutant BRAFV600E-induced senescence and found that these cells exhibited increased incorporation of pyruvate into the tricarboxylic acid (TCA) cycle and elevated redox stress. This increase in mitochondrial oxidative metabolism in response to OIS was mediated by activation of pyruvate dehydrogenase (PDH), a gatekeeper enzyme that links glycolysis to the TCA cycle and is regulated by phosphorylation. Induction of PDH activity in OIS cells was associated with downregulation of pyruvate dehydrogenase kinase 1 (PDK1), which inhibits PDH via phosphorylation, and elevated expression of pyruvate dehydrogenase phosphatase 2 (PDP2), which stimulates PDH via dephosphorylation. Knockdown of PDP2 or restoration of PDK1 expression in cells undergoing OIS resulted in increased phosphorylation and suppression of PDH, decreased oxidative metabolism, and bypass of BRAFV600E-induced senescence. In addition, PDK1 expression in BRAFV600E-expressing melanocytes was sufficient to overcome OIS and induce tumor formation in vivo, suggesting that PDK1 functions as an oncogene. Consistent with this idea, depletion of PDK1 triggered growth arrest and promoted PDH activity in nontransformed melanocytes and prevented melanoma tumor initiation in mice. Furthermore, PDK1 downregulation induced regression of established melanomas and enhanced the sensitivity of BRAF-mutant melanoma cells, including drug resistant subpopulations, to BRAF inhibition, suggesting that PDK1 inhibitors may synergize with BRAF inhibitors to stimulate melanoma cell death. These results establish PDH-driven metabolic rewiring as a critical mediator of OIS and suggest that targeted inhibition of PDK1, alone or in combination with BRAF inhibitors, may provide therapeutic benefit in patients with melanoma.
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