title: Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression.
abstract: 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.
authors: Origins of Cancer Laboratory, Centenary Institute, Newtown, NSW, Australia.
authors: Qian
authors: Q
authors: Wang
authors: Charles G
authors: CG
authors: Bailey
authors: Cynthia
authors: C
authors: Ng
authors: Jessamy
authors: J
authors: Tiffen
authors: Annora
authors: A
authors: Thoeng
authors: Vineet
authors: V
authors: Minhas
authors: Melanie L
authors: ML
authors: Lehman
authors: Stephen C
authors: SC
authors: Hendy
authors: Grant
authors: G
authors: Buchanan
authors: Colleen C
authors: CC
authors: Nelson
authors: John E J
authors: JE
authors: Rasko
authors: Jeff
authors: J
authors: Holst
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C497109:ATF4 protein, human; D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D000598:Amino Acids, Cyclic; D027283:Large Neutral Amino Acid-Transporter 1; D011944:Receptors, Androgen; C469951:SLC7A6 protein, human; D051701:Activating Transcription Factor 4; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases