Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer

Abstract

Metabolic 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 of SDHB induces 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 progression in 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.

Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior

“…While this lack of specificity is most frequently evidenced by in vitro phosphorylation effects, where the drugs can act at their highest potency on purified and often recombinant kinases, within the intracellular milieu, conditions and interactions with other proteins or cell constituents may afford different or even more selective inhibition profiles ( Knight and Shokat, 2005 ; Smyth and Collins, 2009 ). Indeed, other Cdk5 inhibitors in this class of molecules have been shown to be more selective for Cdk5 than Cdk1/2 in cultured cells ( Pozo et al, 2013 ; Gupta et al, 2022 ). However, any off-target or toxic effects of systemic inhibition of Cdk2 by 25–106 remain unknown.…”