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J Natl Cancer Inst. 2013 Oct 2;105(19):1463-73. doi: 10.1093/jnci/djt241. Epub 2013 Sep 19.

Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development.

Author information

1
Affiliations of authors: Origins of Cancer Laboratory (QW, JT, JH) and Gene & Stem Cell Therapy Program (QW, JT, CGB, WR, CM, YF, JEJR, JH), Centenary Institute, Camperdown, Australia; Sydney Medical School, University of Sydney, Sydney, Australia (QW, JT, CGB, WR, CM, YF, JEJR, JH); Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada (MLL, LF, EL, MG, CCN); Cancer Biology Group, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, Australia (GB); Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Brisbane, Australia (CCN, MLL); Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, Australia (JEJR).

Abstract

BACKGROUND:

L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth.

METHODS:

We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided.

RESULTS:

LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4-7 months of neoadjuvant hormone therapy (4-7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo.

CONCLUSION:

Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

PMID:
24052624
DOI:
10.1093/jnci/djt241
[Indexed for MEDLINE]

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