PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Galbraith, L. C.A., Mui, E., Nixon, C., Hedley, A., Strachan, D., MacKay, G., Sumpton, D., Sansom, O. J. , Leung, H. Y. and Ahmad, I. (2021) PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer. Oncogene, 40(13), pp. 2355-2366. (doi: 10.1038/s41388-021-01707-7) (PMID:33654198) (PMCID:PMC8016665)

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Abstract

Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK Clinician Scientist Fellowship award to (C49745/A19661; IA) and CRUK core award to CRUK Beatson Institute A17196 (OJS, CN, AH, DS, DS, & GM).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Nixon, Mr Colin and Leung, Professor Hing and Strachan, Mr David and Mui, Mr Ernest and Sumpton, Mr David and Mackay, Dr Gillian and Galbraith, Dr Laura and Sansom, Professor Owen
Authors: Galbraith, L. C.A., Mui, E., Nixon, C., Hedley, A., Strachan, D., MacKay, G., Sumpton, D., Sansom, O. J., Leung, H. Y., and Ahmad, I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncogene
Publisher:Springer
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:02 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Oncogene 40(13): 2355-2366
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172068Identification and Validation of New Therapeutic Targets in Enzalutamide-Resistant Prostate CancerImran AhmadCancer Research UK (CRUK)C49745/A19661Institute of Cancer Sciences