- Poster presentation
- Open Access
Inhibition of glutamine uptake regulates mTORC1, glutamine metabolism and cell growth in prostate cancer
Cancer & Metabolism volume 2, Article number: P27 (2014)
Amino acids such as glutamine are important for tumor cell growth, survival and metabolism. There is renewed interest in glutamine metabolism due to the importance of reductive carboxylation in cancer. The amino acid transporter ASCT2 (SLC1A5) mediates uptake of glutamine in cancer cells. We have recently reported that ASCT2 expression is significantly upregulated in melanoma, and ASCT2 inhibition significantly decreases glutamine uptake, cell growth, cell cycle and mTORC1 pathway activation . We have previously shown that ASCT2 expression is regulated by the androgen receptor in prostate cancer , and in this current study we further examine ASCT2 expression levels in prostate cancer. Our specific aim was to determine the impact of inhibiting ASCT2-mediated glutamine uptake and metabolism on cell growth.
Materials and methods
We have assessed the role of ASCT2 in prostate cancer using: (1) tissue microarray analysis of ASCT2 protein expression in patients before and after neoadjuvant hormone therapy, (2) cell lines (LNCaP and PC-3) and (3) xenograft (PC-3) models in vivo. Glutamine uptake, cell growth, cell cycle, mTORC1 pathway and glutamine metabolism pathways were assessed using a variety of ASCT2 inhibitors and shRNA mediated ASCT2 knockdown.
ASCT2 is highly expressed in primary prostate cancer, but levels decrease after neoadjuvant hormone therapy, before increasing again in recurrent disease. Inhibition of ASCT2 function by benzylserine led to decreases in glutamine uptake, glutamine metabolism (oxygen consumption rate, glutamine oxidation and lipogenesis), cell cycle progression, mTORC1 pathway activation and cell growth. These data were confirmed after shRNA-mediated ASCT2 knockdown in vitro. Furthermore, shRNA knockdown in PC-3 cell xenografts led to a significant reduction in tumor growth in vivo.
ASCT2-mediated glutamine uptake is essential for multiple pathways including glutamine metabolism and mTORC1 signaling, thereby regulating cellular energy, protein synthesis and cell growth. As such, ASCT2 is a putative therapeutic target in prostate cancer.
Wang Q, Beaumont KA, Otte NJ, Font J, Bailey CG, van Geldermalsen M, Sharp DM, Tiffen JC, Ryan RM, Jormakka M, Haass NK, Rasko JEJ, Holst J: Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer. 2014, Epub 17 Feb
Wang Q, Tiffen J, Bailey CG, Lehman ML, Ritchie W, Fazli L, Metierre C, Feng Y, Li E, Gleave M, Buchanan G, Nelson CC, Rasko JEJ, Holst J: Targeting amino acid transport in metastatic castration-resistant prostate cancer: Effects on cell cycle, cell growth and tumor development. J Natl Cancer Inst. 2013, 105: 1463-1473. 10.1093/jnci/djt241.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Wang, Q., Hardie, RA., Balaban, S. et al. Inhibition of glutamine uptake regulates mTORC1, glutamine metabolism and cell growth in prostate cancer. Cancer Metab 2 (Suppl 1), P27 (2014). https://doi.org/10.1186/2049-3002-2-S1-P27
- Prostate Cancer
- Glutamine Metabolism
- mTORC1 Signaling
- Primary Prostate Cancer