Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development

J Pathol. 2015 Jul;236(3):278-89. doi: 10.1002/path.4518. Epub 2015 Apr 7.

Abstract

Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down-regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer.

Keywords: ASCT2; SLC1A5; cell cycle; glutamine; metabolism; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / antagonists & inhibitors
  • Amino Acid Transport System ASC / genetics*
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • Biological Transport
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Fatty Acids / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Glutamine / metabolism*
  • Heterografts
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Minor Histocompatibility Antigens
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Neoplasm Metastasis
  • Oxygen / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control
  • RNA, Small Interfering
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Amino Acid Transport System ASC
  • Fatty Acids
  • Minor Histocompatibility Antigens
  • Multiprotein Complexes
  • RNA, Small Interfering
  • SLC1A5 protein, human
  • Glutamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Oxygen