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
Authors | 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 and Bibb, James A. |
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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 |
Year | 2022 |
Journal | Cell Reports |
Journal citation | 40 (7), p. Article 111218 |
Publisher | Cell Press |
ISSN | 2211-1247 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.celrep.2022.111218 |
PubMed ID | 35977518 |
Scopus EID | 2-s2.0-85136062616 |
PubMed Central ID | PMC9822535 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-20 |
Funder | SDHB 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 | |
Deposited | 31 Jan 2023 |
Grant ID | MH116896 |
MH126948 | |
P30 CA013148 | |
S10 OD028498-01 | |
1145265 | |
P30 DK-079626 |
https://acuresearchbank.acu.edu.au/item/8yq2v/genetic-impairment-of-succinate-metabolism-disrupts-bioenergetic-sensing-in-adrenal-neuroendocrine-cancer
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License: CC BY 4.0 | |
File access level: Open |
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