Androgen Receptor and Nutrient Signaling Pathways Coordinate the Demand for Increased Amino Acid Transport during Prostate Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 24; pp. 7525 - 7536
• Main Authors: QIAN WANG, BAILEY, Charles G, RASKO, John E. J, HOLST, Jeff, NG, Cynthia, TIFFEN, Jessamy, THOENG, Annora, MINHAS, Vineet, LEHMAN, Melanie L, HENDY, Stephen C, BUCHANAN, Grant, NELSON, Colleen C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-12-2011
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Amino Acid Transport Systems, Basic - genetics; Amino Acid Transport Systems, Basic - metabolism; Amino Acids - metabolism; Amino Acids, Cyclic - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Biological Transport - drug effects; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; HEK293 Cells; Humans; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Transplantation, Heterologous; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Malignant tumor; Signal transduction; Signaling pathway; Aminoacid; Tumor progression; Androgen receptor; Nutrient; Transport; Male genital diseases; Prostate cancer; Cancer; Hormonal receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-1821

L-Type amino acid transporters such as LAT1 and LAT3 mediate the uptake of essential amino acids. Here, we report that prostate cancer cells coordinate the expression of LAT1 and LAT3 to maintain sufficient levels of leucine needed for mTORC1 signaling and cell growth. Inhibiting LAT function was sufficient to decrease cell growth and mTORC1 signaling in prostate cancer cells. These cells maintained levels of amino acid influx through androgen receptor-mediated regulation of LAT3 expression and ATF4 regulation of LAT1 expression after amino acid deprivation. These responses remained intact in primary prostate cancer, as indicated by high levels of LAT3 in primary disease, and by increased levels of LAT1 after hormone ablation and in metastatic lesions. Taken together, our results show how prostate cancer cells respond to demands for increased essential amino acids by coordinately activating amino acid transporter pathways vital for tumor outgrowth.