Loading...
Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer
Gupta, Priyanka Strange, Keehn Telange, Rahul Guo, Ailan Hatch, Heather Sobh, Amin Elie, Jonathan Carter, Angela M. Totenhagen, John Tan, Chunfeng
Gupta, Priyanka
Strange, Keehn
Telange, Rahul
Guo, Ailan
Hatch, Heather
Sobh, Amin
Elie, Jonathan
Carter, Angela M.
Totenhagen, John
Tan, Chunfeng
Author
Gupta, Priyanka
Strange, Keehn
Telange, Rahul
Guo, Ailan
Hatch, Heather
Sobh, Amin
Elie, Jonathan
Carter, Angela M.
Totenhagen, John
Tan, Chunfeng
Sonawane, Yogesh A.
Neuzil, Jiri
Natarajan, Amarnath
Ovens, Ashley J.
Oakhill, Jonathan S.
Wiederhold, Thorsten
Pacak, Karel
Ghayee, Hans K.
Meijer, Laurent
Reddy, Sushanth
Bibb, James A.
Strange, Keehn
Telange, Rahul
Guo, Ailan
Hatch, Heather
Sobh, Amin
Elie, Jonathan
Carter, Angela M.
Totenhagen, John
Tan, Chunfeng
Sonawane, Yogesh A.
Neuzil, Jiri
Natarajan, Amarnath
Ovens, Ashley J.
Oakhill, Jonathan S.
Wiederhold, Thorsten
Pacak, Karel
Ghayee, Hans K.
Meijer, Laurent
Reddy, Sushanth
Bibb, James A.
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
neuroendocrine tumor, pheochromocytoma, SDHB, Cdk5, AMPK, PRKAG2, p53, Warburg effect, cancer bioenergetics, senescence
Date
2022
Type
Journal article
Journal
Cell Reports
Book
Volume
40
Issue
7
Page Range
1-20
Article Number
Article 111218
ACU Department
Non-faculty
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
File Access
Open
Open
Open