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

Oncogene. 2021 Apr;40(13):2355-2366. doi: 10.1038/s41388-021-01707-7. Epub 2021 Mar 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics
  • Exportin 1 Protein
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Karyopherins / genetics
  • Lipid Metabolism / genetics
  • Male
  • Mice
  • Mitochondria / genetics
  • Organelle Biogenesis
  • PPAR gamma / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / genetics*
  • Receptors, Cytoplasmic and Nuclear / genetics

Substances

  • Karyopherins
  • PPAR gamma
  • PPARG protein, human
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Receptors, Cytoplasmic and Nuclear
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt