Please use this identifier to cite or link to this item:
|Scopus||Web of Science®||Altmetric|
|Title:||Targeting amino acid transport in metastatic castration-resistant prostate cancer: Effects on cell cycle, cell growth, and tumor development|
|Citation:||Journal of the National Cancer Institute, 2013; 105(19):1463-1473|
|Publisher:||Oxford Univ Press Inc|
|Qian Wang, Jessamy Tiffen, Charles G. Bailey, Melanie L. Lehman, William Ritchie, Ladan Fazli, Cynthia Metierre, Yue (Julie) Feng, Estelle Li, Martin Gleave, Grant Buchanan, Colleen C. Nelson, John E. J. Rasko, Jeff Holst|
|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.|
|Keywords:||Animals; Humans; Mice; Prostatic Neoplasms; Neoplasms, Hormone-Dependent; Multiprotein Complexes; Amino Acids; Leucine; Amino Acid Transport Systems, Basic; Receptors, Androgen; Antineoplastic Agents, Hormonal; Neoadjuvant Therapy; Orchiectomy; Protein Array Analysis; Luminescent Measurements; Xenograft Model Antitumor Assays; Signal Transduction; Cell Cycle; Gene Expression Regulation, Neoplastic; Up-Regulation; Biological Transport; Computer Simulation; Male; Activating Transcription Factor 4; Gene Knockdown Techniques; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1|
|Rights:||© The Author 2013|
|Appears in Collections:||Medicine publications|
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.