Androgen Receptor and Nutrient Signaling Pathways Coordinate the Demand for Increased Amino Acid Transport during Prostate Cancer Progression
Androgen Receptor and Nutrient Signaling Pathways Coordinate the Demand for Increased Amino Acid Transport during Prostate Cancer Progression
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DOI：
10.1158/0008-5472.can-11-1821
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Holst, Jeff
中科院分区：
文献类型：
--
作者：
Wang, Qian;Bailey, Charles G.;Holst, Jeff
l型氨基酸转运体如LAT1和LAT3介导必需氨基酸的摄取。在这里，我们报道了前列腺癌细胞协调LAT1和LAT3的表达，以维持mTORC1信号传导和细胞生长所需的足够水平的亮氨酸。抑制LAT功能足以降低前列腺癌细胞的细胞生长和mTORC1信号传导。氨基酸剥夺后，这些细胞通过雄激素受体介导的LAT3表达调控和ATF4对LAT1表达的调控来维持氨基酸内流水平。这些反应在原发性前列腺癌中保持不变，如原发性疾病中LAT3水平高，激素消融后和转移性病变中LAT1水平升高所示。综上所述，我们的研究结果表明前列腺癌细胞如何通过协调激活对肿瘤生长至关重要的氨基酸转运途径来响应对必需氨基酸增加的需求。癌症Res;71 (24);7525 - 36。(c) 2011年aacr。
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. Cancer Res; 71(24); 7525-36. (C) 2011 AACR.