Targeting ASCT2-mediated Glutamine Uptake Blocks Prostate Cancer Growth and Tumour Development

Overview

Journal J Pathol

Specialty Pathology

Date 2015 Feb 20

PMID 25693838

Citations 196

Authors

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 E J Rasko

Jeff Holst

Affiliations

Soon will be listed here.

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.

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