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

Qian Wang, Rae Anne Hardie, Andrew J. Hoy, Michelle Van Geldermalsen, Dadi Gao, Ladan Fazli, Martin C. Sadowski, Seher Balaban, Mark Schreuder, Rajini Nagarajah, Justin J L Wong, Cynthia Metierre, Natalia Pinello, Nicholas J. Otte, Melanie L. Lehman, Martin Gleave, Colleen C. Nelson, Charles G. Bailey, William Ritchie, John Ej RaskoJeff Holst*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

166 Citations (Scopus)
6 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)278-289
Number of pages12
JournalJournal of Pathology
Volume236
Issue number3
DOIs
Publication statusPublished - 1 Jul 2015
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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