Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

• Keywords
• AMPK, CP: Cancer, CP: Metabolism, Cdk5, PRKAG2, SDHB, Warburg effect, cancer bioenergetics, neuroendocrine tumor, p53, pheochromocytoma, senescence,
• MeSH
• Adenylate Kinase * metabolism   MeSH
• Cyclin-Dependent Kinase 5 metabolism   MeSH
• Energy Metabolism MeSH
• Phosphorylation MeSH
• Glycogen Synthase Kinase 3 metabolism   MeSH
• Mice MeSH
• Carcinoma, Neuroendocrine * MeSH
• Succinates MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Adenylate Kinase * MeSH
• Cyclin-Dependent Kinase 5 MeSH
• Glycogen Synthase Kinase 3 MeSH
• Succinates MeSH