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

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

Language

English

Publication Date

8-16-2022

Journal

Cell Reports

DOI

10.1016/j.celrep.2022.111218

PMID

35977518

PMCID

PMC9822535

PubMedCentral® Posted Date

1-6-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

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

Adenylate Kinase, Animals, Carcinoma, Neuroendocrine, Cyclin-Dependent Kinase 5, Energy Metabolism, Glycogen Synthase Kinase 3, Mice, Phosphorylation, Succinates, AMPK, CP: Cancer, CP: Metabolism, Cdk5, PRKAG2, SDHB, Warburg effect, cancer bioenergetics, neuroendocrine tumor, p53, pheochromocytoma, senescence

Published Open-Access

yes

Recommended Citation

Gupta, Priyanka; Strange, Keehn; Telange, Rahul; et al., "Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer" (2022). Faculty, Staff and Student Publications. 3136.
https://digitalcommons.library.tmc.edu/uthmed_docs/3136