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 E. J. Rasko; Jeff Holst

doi:10.1002/path.4518

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 E. J. RaskoJeff Holst^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	278-289
Number of pages	12
Journal	Journal of Pathology
Volume	236
Issue number	3
DOIs	https://doi.org/10.1002/path.4518
Publication status	Published - 1 Jul 2015
Externally published	Yes

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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Wang, Q., Hardie, R. A., Hoy, A. J., Van Geldermalsen, M., Gao, D., Fazli, L., Sadowski, M. C., Balaban, S., Schreuder, M., Nagarajah, R., Wong, J. J. L., Metierre, C., Pinello, N., Otte, N. J., Lehman, M. L., Gleave, M., Nelson, C. C., Bailey, C. G., Ritchie, W., ... Holst, J. (2015). Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. Journal of Pathology, 236(3), 278-289. https://doi.org/10.1002/path.4518

@article{b9549a2705a24d61ab192e9416028310,

title = "Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development",

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.",

author = "Qian Wang and Hardie, {Rae Anne} and Hoy, {Andrew J.} and {Van Geldermalsen}, Michelle and Dadi Gao and Ladan Fazli and Sadowski, {Martin C.} and Seher Balaban and Mark Schreuder and Rajini Nagarajah and Wong, {Justin J. L.} and Cynthia Metierre and Natalia Pinello and Otte, {Nicholas J.} and Lehman, {Melanie L.} and Martin Gleave and Nelson, {Colleen C.} and Bailey, {Charles G.} and William Ritchie and Rasko, {John E. J.} and Jeff Holst",

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.",

year = "2015",

month = jul,

day = "1",

doi = "10.1002/path.4518",

language = "English",

volume = "236",

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Wang, Q, Hardie, RA, Hoy, AJ, Van Geldermalsen, M, Gao, D, Fazli, L, Sadowski, MC, Balaban, S, Schreuder, M, Nagarajah, R, Wong, JJL, Metierre, C, Pinello, N, Otte, NJ, Lehman, ML, Gleave, M, Nelson, CC, Bailey, CG, Ritchie, W, Rasko, JEJ & Holst, J 2015, 'Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development', Journal of Pathology, vol. 236, no. 3, pp. 278-289. https://doi.org/10.1002/path.4518

TY - JOUR

T1 - Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development

AU - Wang, Qian

AU - Hardie, Rae Anne

AU - Hoy, Andrew J.

AU - Van Geldermalsen, Michelle

AU - Gao, Dadi

AU - Fazli, Ladan

AU - Sadowski, Martin C.

AU - Balaban, Seher

AU - Schreuder, Mark

AU - Nagarajah, Rajini

AU - Wong, Justin J. L.

AU - Metierre, Cynthia

AU - Pinello, Natalia

AU - Otte, Nicholas J.

AU - Lehman, Melanie L.

AU - Gleave, Martin

AU - Nelson, Colleen C.

AU - Bailey, Charles G.

AU - Ritchie, William

AU - Rasko, John E. J.

AU - Holst, Jeff

N1 - 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.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84930482603&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/nhmrc/1051820

U2 - 10.1002/path.4518

DO - 10.1002/path.4518

M3 - Article

C2 - 25693838

AN - SCOPUS:84930482603

SN - 0022-3417

VL - 236

SP - 278

EP - 289

JO - Journal of Pathology

JF - Journal of Pathology

IS - 3

ER -

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

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