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Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer
P. Gupta, K. Strange, R. Telange, A. Guo, H. Hatch, A. Sobh, J. Elie, AM. Carter, J. Totenhagen, C. Tan, YA. Sonawane, J. Neuzil, A. Natarajan, AJ. Ovens, JS. Oakhill, T. Wiederhold, K. Pacak, HK. Ghayee, L. Meijer, S. Reddy, JA. Bibb
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, N.I.H., Intramural
Grantová podpora
P50 CA127297
NCI NIH HHS - United States
P30 CA013148
NCI NIH HHS - United States
S10 OD028498
NIH HHS - United States
P30 DK079626
NIDDK NIH HHS - United States
NLK
Cell Press Free Archives
od 2012
Directory of Open Access Journals
od 2012
Free Medical Journals
od 2012
Freely Accessible Science Journals
od 2012-01-26
Open Access Digital Library
od 2012-01-01
Open Access Digital Library
od 2012-01-26
- MeSH
- adenylátkinasa * metabolismus MeSH
- cyklin-dependentní kinasa 5 metabolismus MeSH
- energetický metabolismus MeSH
- fosforylace MeSH
- kinasa 3 glykogensynthasy metabolismus MeSH
- myši MeSH
- neuroendokrinní karcinom * MeSH
- sukcináty MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
Cell Signaling Technology Danvers MA 01923 USA
Department of Hematology St Jude Children's Research Hospital Memphis TN 38105 USA
Institute of Biotechnology Czech Academy of Sciences Prague West 252 50 Czech Republic
Mary MacKillop Institute for Health Research Australian Catholic University Melbourne VIC Australia
Metabolic Signalling Laboratory St Vincent's Institute of Medical Research Fitzroy VIC Australia
Perha Pharmaceuticals Hôtel de Recherche Perharidy Peninsula 29680 Roscoff France
School of Pharmacy Medical Science Griffith University Southport QLD 4222 Australia
Citace poskytuje Crossref.org
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- $a 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.
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