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

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 (PGC1 alpha) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1 alpha 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 PGC1 alpha 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.

Automated summary

The study demonstrates the association between PPARG and metastasis in prostate cancer, with PPARG over-expression leading to increased levels of AKT3, which in turn enhances PGC1α localization in the nucleus, driving mitochondrial biogenesis and providing higher energetic output for tumor cell progression towards metastasis through EMT.