Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development

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 nutrie...

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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2013-10, Vol.105 (19), p.1463-1473
Main Authors: QIAN WANG, TIFFEN, Jessamy, BUCHANAN, Grant, NELSON, Colleen C, RASKO, John E. J, HOLST, Jeff, BAILEY, Charles G, LEHMAN, Melanie L, RITCHIE, William, FAZLI, Ladan, METIERRE, Cynthia, YUE FENG, LI, Estelle, GLEAVE, Martin
Format: Article
Language:English
Subjects:
Activating Transcription Factor 4 - drug effects
Activating Transcription Factor 4 - metabolism
Amino Acid Transport Systems, Basic - antagonists & inhibitors
Amino Acid Transport Systems, Basic - genetics
Amino Acid Transport Systems, Basic - metabolism
Amino acids
Amino Acids - metabolism
Animals
Antineoplastic Agents, Hormonal - pharmacology
Antineoplastic Agents, Hormonal - therapeutic use
Biological and medical sciences
Biological Transport - drug effects
Cell Cycle - drug effects
Computer Simulation
Gene Expression Regulation, Neoplastic - drug effects
Gene Knockdown Techniques
Humans
Leucine - antagonists & inhibitors
Leucine - metabolism
Luminescent Measurements
Male
Mechanistic Target of Rapamycin Complex 1
Medical research
Medical sciences
Mens health
Metastasis
Mice
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Multiprotein Complexes - metabolism
Neoadjuvant Therapy - methods
Neoplasms, Hormone-Dependent - drug therapy
Neoplasms, Hormone-Dependent - physiopathology
Nephrology. Urinary tract diseases
Orchiectomy
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Prostatic Neoplasms - physiopathology
Protein Array Analysis
Receptors, Androgen - drug effects
Receptors, Androgen - metabolism
Signal Transduction - drug effects
TOR Serine-Threonine Kinases - metabolism
Tumors
Tumors of the urinary system
Up-Regulation - drug effects
Urinary tract. Prostate gland
Xenograft Model Antitumor Assays
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Summary: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. 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. 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. 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.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djt241