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.
Highlights
Prostate cancer (PC) is the most common cancer in adult males in the developed world and the second leading cause of cancer deaths [1]
In this work we have been able to identify a novel effector of Peroxisome Proliferator-Activated Receptor Gamma (PPARG), AKT serine/ threonine kinase 3 (AKT3), which elicits its effects through the AKT3-PGC1α axis
It appears that the role of PPARG within the prostate tumour environment is critical for survival within the in vivo system due to the inherent pressures and stresses of the tumour environment
Summary
Prostate cancer (PC) is the most common cancer in adult males in the developed world and the second leading cause of cancer deaths [1]. Further analysis of prostate tumour lysates revealed that up-regulation of PPARG correlated with increased levels of its downstream metabolic effectors such as Fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) [4, 5]. This was associated with increased lung and lymph-nodes metastasis, suggesting a way of stratifying patients with PPARG or FASN activation to targeted treatments for their aggressive disease. In this study we identify a previously unknown role for PPARG in up-regulating AKT3, which promotes PGC1α localisation to the nucleus and increases mitochondrial mass and function, increasing ATP levels, tumour growth and metastasis. For technical reasons only five mice were available at endpoint for mice from the KO1 and KO2 cohorts
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