@article{bb00ce7a9da1411c8f9dd08d562a0313,
title = "Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer",
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 = "AMPK, CP: Cancer, CP: Metabolism, Cdk5, PRKAG2, SDHB, Warburg effect, cancer bioenergetics, neuroendocrine tumor, p53, pheochromocytoma, senescence",
author = "Priyanka Gupta and Keehn Strange and Rahul Telange and Ailan Guo and Heather Hatch and Amin Sobh and Jonathan Elie and Carter, {Angela M.} and John Totenhagen and Chunfeng Tan and Sonawane, {Yogesh A.} and Jiri Neuzil and Amarnath Natarajan and Ovens, {Ashley J.} and Oakhill, {Jonathan S.} and Thorsten Wiederhold and Karel Pacak and Ghayee, {Hans K.} and Laurent Meijer and Sushanth Reddy and Bibb, {James A.}",
note = "Funding Information: We thank S. Thomas for assistance with MRI, E. Daniel for technical expertise, S. Barnes for LC-MS succinate measurements, D. Pollack for assistance in measuring mouse blood pressure, L. Bibb and SouthernBiotech for phosphorylation state-specific antibodies, and Pfizer for CP681301. This research was supported by the SDHB Para/Pheo Coalition and the Neuroendocrine Tumor Research Foundation (NETRF, J.A.B.). Portions of this work were also facilitated by the NIH (MH116896, MH126948, J.A.B.), the Robert E Reed Gastrointestinal Oncology Research Foundation, an American Cancer Society Institutional Research Grant Junior Faculty Development Award (S.R.), and Postdoctoral Fellowship (A.M.C.). This research was supported, in part, by Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH (K.P.); the Gatorade Trust through funds by the University of Florida, Department of Medicine (H.K.G.); and by a Eurostars grant (CYST-ARREST, L.M.). Studies were also supported by the National Cancer Institute Cancer Center Support Grant P30 CA013148 (UAB O'Neal Comprehensive Cancer Center). It was also supported by S10 OD028498-01 (UAB Preclinical Imaging Shared Facility). Some chemical synthesis was also supported by NCI SPORE P50 CA127297 (A.N. Eppley Institute for Research in Cancer and Allied Disease). This work was also supported in part by grant 1145265 from the National Health and Medical Research Council (NHMRC, to J.S.O.), St Vincent's Institute of Medical Research (Australia), and the Victorian Government's Operational Infrastructure Support Program. We are grateful to the UAB Diabetes Research Center (NIH P30 DK-079626) for providing core services. J.A.B. and P.G. conceptualized the project. P.G. designed and performed the experiments, analyzed the data, and wrote the original draft. L.M. A.N. J.E. and Y.A.S. provided Cdk5 inhibitors. K.S. R.T. C.T. H.K.G. H.H. A.S. J.N. J.S.O. A.J.O. A.M.C. J.T. K.P. A.G. and T.W. provided reagents or assisted with the experiments. J.A.B. S.R. K.P. and H.K.G. provided conceptual input. J.A.B. oversaw all study design, data analysis, and review and editing of the manuscript. J.A.B. and S.R. acquired funding and supervised the study. All authors discussed the results and commented on the manuscript. The authors declare no competing interests. Funding Information: We thank S. Thomas for assistance with MRI, E. Daniel for technical expertise, S. Barnes for LC-MS succinate measurements, D. Pollack for assistance in measuring mouse blood pressure, L. Bibb and SouthernBiotech for phosphorylation state-specific antibodies, and Pfizer for CP681301. This research was supported by the SDHB Para/Pheo Coalition and the Neuroendocrine Tumor Research Foundation (NETRF, J.A.B.). Portions of this work were also facilitated by the NIH ( MH116896 , MH126948 , J.A.B.), the Robert E Reed Gastrointestinal Oncology Research Foundation , an American Cancer Society Institutional Research Grant Junior Faculty Development Award (S.R.), and Postdoctoral Fellowship (A.M.C.). This research was supported, in part, by Intramural Research Program of the Eunice Kennedy Shriver NICHD , NIH (K.P.); the Gatorade Trust through funds by the University of Florida , Department of Medicine (H.K.G.); and by a Eurostars grant (CYST-ARREST, L.M.). Studies were also supported by the National Cancer Institute Cancer Center Support Grant P30 CA013148 (UAB O{\textquoteright}Neal Comprehensive Cancer Center). It was also supported by S10 OD028498-01 ( UAB Preclinical Imaging Shared Facility). Some chemical synthesis was also supported by NCI SPORE P50 CA127297 (A.N., Eppley Institute for Research in Cancer and Allied Disease). This work was also supported in part by grant 1145265 from the National Health and Medical Research Council (NHMRC, to J.S.O.), St Vincent{\textquoteright}s Institute of Medical Research (Australia), and the Victorian Government {\textquoteright}s Operational Infrastructure Support Program. We are grateful to the UAB Diabetes Research Center (NIH P30 DK-079626 ) for providing core services. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = aug,
day = "16",
doi = "10.1016/j.celrep.2022.111218",
language = "English (US)",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}