Dasgupta Subhamoy, Putluri Nagireddy, Long Weiwen, Zhang Bin, Wang Jianghua, Kaushik Akash K, Arnold James M, Bhowmik Salil K, Stashi Erin, Brennan Christine A, Rajapakshe Kimal, Coarfa Cristian, Mitsiades Nicholas, Ittmann Michael M, Chinnaiyan Arul M, Sreekumar Arun, O'Malley Bert W
J Clin Invest. 2015 Mar 2;125(3):1174-88. doi: 10.1172/JCI76029. Epub 2015 Feb 9.
Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2-driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer.
代谢途径重编程是癌细胞生长和存活的一个标志，并支持这些快速分裂细胞的合成代谢和能量需求。肿瘤代谢程序的潜在调节因子尚未完全了解；然而，这些因子具有作为癌症治疗靶点的潜力。在这里，我们确定致癌转录共调节因子类固醇受体共激活因子2（SRC-2，也称为NCOA2）的上调驱动谷氨酰胺依赖性从头脂肪生成，这支持肿瘤细胞的存活和最终转移。SRC-2在多种肿瘤中高度升高，尤其是在前列腺癌中，在评估的37%的转移性肿瘤中，SRC-2被扩增并过度表达。在前列腺癌细胞中，SRC-2通过逆行三羧酸循环刺激α-酮戊二酸的还原羧化以生成柠檬酸，促进脂肪生成和谷氨酰胺代谢重编程。谷氨酰胺介导的营养信号通过mTORC1依赖性磷酸化激活SRC-2，然后通过共激活SREBP-1触发下游转录反应，SREBP-1随后增强脂肪生成酶的表达。与局限性肿瘤相比，人类前列腺肿瘤的代谢谱分析发现转移性肿瘤中SRC-2驱动的代谢特征大幅增加，进一步表明SRC-2是癌症转移的一个重要代谢协调因子。此外，在小鼠模型中抑制SRC-2严重减弱了前列腺癌的存活、生长和转移。总之，这些结果表明SRC-2途径具有作为前列腺癌治疗靶点的潜力。
