Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: molecular basis and pathophysiological consequences

Oncogene. 2017 Oct 26;36(43):6030-6040. doi: 10.1038/onc.2017.216. Epub 2017 Jul 3.

Abstract

Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer.

MeSH terms

  • Carcinogenesis / genetics
  • Carnitine / metabolism
  • Carnitine O-Palmitoyltransferase / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Fatty Acids / genetics
  • Fatty Acids / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • MicroRNAs / genetics*
  • Oxidation-Reduction
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology

Substances

  • Fatty Acids
  • MIRN124 microRNA, human
  • MIRN378 microRNA, human
  • Membrane Transport Proteins
  • MicroRNAs
  • Mirn129 microRNA, human
  • SLC25A20 protein, human
  • CPT1A protein, human
  • Carnitine O-Palmitoyltransferase
  • Carnitine