PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription

Carcinogenesis. 2017 Jul 1;38(7):748-755. doi: 10.1093/carcin/bgx035.

Abstract

Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment.

MeSH terms

  • Amino Acid Transport System ASC / genetics*
  • Amino Acid Transport System ASC / metabolism
  • Amino Acids / metabolism
  • Animals
  • Biosynthetic Pathways
  • Energy Metabolism / genetics
  • Glucose / metabolism
  • Glucose Transporter Type 1 / genetics*
  • Glucose Transporter Type 1 / metabolism
  • HCT116 Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • TOR Serine-Threonine Kinases / genetics*
  • Transcription, Genetic

Substances

  • Amino Acid Transport System ASC
  • Amino Acids
  • Glucose Transporter Type 1
  • Minor Histocompatibility Antigens
  • PPAR gamma
  • SLC1A5 protein, human
  • SLC2A1 protein, human
  • TOR Serine-Threonine Kinases
  • Glucose