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

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 ReddyJames A. Bibb

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number111218
JournalCell Reports
DOIs
StateAccepted/In press - 2022

Keywords

  • AMPK
  • cancer bioenergetics
  • Cdk5
  • CP: Cancer
  • CP: Metabolism
  • neuroendocrine tumor
  • p53
  • pheochromocytoma
  • PRKAG2
  • SDHB
  • senescence
  • Warburg effect

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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