Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer

• DOI: 10.1016/j.celrep.2022.111218
• Publication Date: 2022-08-16T14:50:18Z
• Authors: Priyanka Gupta; Keehn Strange; Rahul Telange; Ailan Guo; Heather Hatch; Amin Sobh; Jonathan Elie; Angela M. Carter; John Totenhagen; Chunfeng Tan; Yogesh A. Sonawane; Jiri Neuzil; Amarnath Natarajan; Ashley J. Ovens; Jonathan S. Oakhill; Thorsten Wiederhold; Karel Pacak; Hans K. Ghayee; Laurent Meijer; Sushanth Reddy; James A. Bibb
• Keywords: AMPK; p53; senescence; Cdk5; Neurology and neuromuscular diseases; Glycogen Synthase Kinase 3; Mice; Endocrinology; Genetics; cancer bioenergetics; Animals; Phosphorylation; Adenylate Kinase; Cyclin-Dependent Kinase 5; Succinates; SDHB; pheochromocytoma; PRKAG2; CP: Metabolism; Carcinoma, Neuroendocrine; 3. Good health; Biological sciences; Warburg effect; Energy Metabolism; CP: Cancer; neuroendocrine tumor

SUMMARYMetabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss ofSDHBinduces the Warburg effect in PC tumors, triggers dysregulation of Ca2+homeostasis, and aberrantly activates calpain and the protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a cascade of phospho- signaling 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 tumor formation. A novel Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking an anti- Warburg effect, cell cycle arrest, and senescence-like phenotype. This therapeutic approach halted tumor progressionin vivo. Thus, we reveal an important novel mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.HighlightsLoss of SDHB function in pheochromocytoma causes Ca2+dysregulation, calpain activation, and aberrant activation of the protein kinase Cdk5.Hyperactive Cdk5 deregulates a GSK3/PRKAG2/AMPKα signaling cascade.p25 overexpression and consequent aberrant Cdk5 activity in chromaffin cells causes pheochromocytoma.Inhibition of Cdk5 activates the PRKAG2/AMPK/p53 signaling to rescue cell senescence and block PC tumor progression.Graphical Abstract