Format

Send to

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

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

Author information

1
Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
2
Sydney Medical School, University of Sydney, NSW, Australia.
3
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
4
Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
5
Bioinformatics, Centenary Institute, Camperdown, NSW, Australia.
6
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
7
Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Australia.
8
Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

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

PMID:
25693838
PMCID:
PMC4973854
DOI:
10.1002/path.4518
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center