Understanding the Molecular Underpinnings of Neuronal Kinase CDK5 mediated Metabolic Vulnerabilities in Neuroendocrine Tumors

Abstract

Background Aberrantly activated neuronal kinase CDK5 invoke alternations in mitochondrial dynamics and metabolic dysfunction associated with neurological disorders. Although pro‐tumorigenic role of CDK5 has been recently defined but there is insufficient data to understand the mechanistic role of CDK5 in cancer associated mitochondrial structure and function. Hypothesis In this study we intend to investigate putative signalling hotspots downstream of aberrantly activated CDK5 in neuroendocrine tumors of adrenal glands called Pheochromocytoma (PC). Approach Our preliminary data for the first time showed deregulation of Ca2+ homeostasis and overexpression of CDK5 and its co‐activators‐p35/25 in malignant PC tumors inflicted with loss‐of‐function mutations in mitochondrial enzyme‐Succinate dehydrogenase B (SDHB). To elucidate role of CDK5 in tumorigenesis, we created a novel bi‐transgenic mouse model where doxycycline inducible overexpression of CDK5/p25 (p25OE) developed organ specific PC lesions. Results Phopshoproteomic analysis on p25OE PC tumors unraveled a tumor suppressive mechanism modulated by novel phosphorylation site on metabolic protein‐PRKAG2 (S‐65). PRKAG2 is a non‐catalytic regulatory subunit of AMP‐activated protein kinase (AMPK). S‐65 site on PRKAG2 were found downregulated in human PC tumors compared to normal adrenal medulla. Further biochemical characterization uncovered CDK5‐GSK3β‐AMPK crosstalk underlying human PC cellular proliferation. Picking CDK5 pocket with a novel CDK5 inhibitor ‘MRT3‐007’ induced anti‐proliferative effects with simultaneous increase in phosphorylation states of PRKAG2(S‐65) / AMPK(T‐172) sites followed by excessive mitochondrial fission. Conclusion These intriguing initial findings set the ground to discover therapeutic vulnerabilities associated with CDK5/p25/PRKAG2/AMPK signaling cascade and Mitochondrial Dynamics in Neuroendocrine tumors. Schematic depiction of working model demonstrating a novel crosstalk between a metabolic sensor ‘PRKAG2/AMPK’ and ‘Mitochondrial Fission’ synapsed via neuronal kinase ‘CDK5/p25’ in Pheochromocytoma (PC tumors) inflicted with mutations in SDHB gene.