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

Journal article


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, ... Bibb, James A.. (2022). Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer. Cell Reports. 40(7), p. Article 111218. https://doi.org/10.1016/j.celrep.2022.111218
AuthorsGupta, 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 and 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.

Keywordsneuroendocrine tumor; pheochromocytoma; SDHB; Cdk5; AMPK; PRKAG2; p53; Warburg effect; cancer bioenergetics; senescence
Year2022
JournalCell Reports
Journal citation40 (7), p. Article 111218
PublisherCell Press
ISSN2211-1247
Digital Object Identifier (DOI)https://doi.org/10.1016/j.celrep.2022.111218
PubMed ID35977518
Scopus EID2-s2.0-85136062616
PubMed Central IDPMC9822535
Open accessPublished as ‘gold’ (paid) open access
Page range1-20
FunderSDHB PheoPara Coalition
Neuroendocrine Tumor Research Foundation
National Institutes of Health (NIH), United States of America
Robert E. Reed Gastrointestinal Oncology Research Foundation
American Cancer Society
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health
University of Florida
Eurostars
National Cancer Institute Cancer Center
University of Alabama
National Health and Medical Research Council (NHMRC)
St Vincent’s Institute of Medical Research
Operational Infrastructure Support (OIS) Program, Victorian Government
Publisher's version
License
File Access Level
Open
Publication process dates
Deposited31 Jan 2023
Grant IDMH116896
MH126948
P30 CA013148
S10 OD028498-01
1145265
P30 DK-079626
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