Targeting glutamine transport to suppress melanoma cell growth

Wang, Qian, Beaumont, Kimberley A., Otte, Nicholas J., Font, Josep, Bailey, Charles G., van Geldermalsen, Michelle, Sharp, Danae M., Tiffen, Jessamy C., Ryan, Renae M., Jormakka, Mika, Haass, Nikolas K., Rasko, John E. J. and Holst, Jeff (2014) Targeting glutamine transport to suppress melanoma cell growth. International Journal of Cancer, 135 5: 1060-1071. doi:10.1002/ijc.28749

Author Wang, Qian
Beaumont, Kimberley A.
Otte, Nicholas J.
Font, Josep
Bailey, Charles G.
van Geldermalsen, Michelle
Sharp, Danae M.
Tiffen, Jessamy C.
Ryan, Renae M.
Jormakka, Mika
Haass, Nikolas K.
Rasko, John E. J.
Holst, Jeff
Title Targeting glutamine transport to suppress melanoma cell growth
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 1097-0215
Publication date 2014-09-01
Year available 2014
Sub-type Article (original research)
DOI 10.1002/ijc.28749
Open Access Status Not yet assessed
Volume 135
Issue 5
Start page 1060
End page 1071
Total pages 12
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Formatted abstract
Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAFWT (C8161 and WM852) and BRAFV600E mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAFWT and BRAFV600E melanoma.
Keyword ASCT2
Amino acid transport
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID PG2910
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 48 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 56 times in Scopus Article | Citations
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Created: Fri, 30 May 2014, 22:24:44 EST by Nikolas Haass on behalf of UQ Diamantina Institute