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JCI:SRC-2依赖性代谢重组调节前列腺癌细胞生存与转移

来源:生物谷 2015-02-11 16:38

                                                                 
2015年2月11日讯  /生物谷BIOON/  --近日,著名国际期刊JCI发表了美国科学家的一项最新研究成果,他们发现转录共调控因子SRC-2在前列腺癌细胞中高表达,并且与原位肿瘤相比,发生转移的肿瘤细胞中SRC-2驱动的代谢相关基因表达更高,该项研究证明了SRC-2驱动的代谢重编程对前列腺癌细胞存活生长和转移至关重要。
 
代谢途径的重编程是癌细胞生长存活的一大特征,能够提供癌细胞快速分裂增殖的合成代谢和能量需求。但目前对肿瘤代谢调控因子的了解仍然不是特别充分,这些因子可能成为靶向治疗癌症的潜在靶点。研究人员发现转录共调控因子SRC-2上调能够驱动谷氨酰胺依赖性的脂质从头合成,对于维持肿瘤细胞存活促进转移具有重要作用。
 
SRC-2在多种肿瘤细胞中均出现表达上调,特别是在前列腺癌,而且在37%发生转移的肿瘤中均有SRC-2的活性增强以及表达增加。在前列腺癌细胞中,SRC-2刺激α酮戊二酸发生还原性羧化作用产生柠檬酸,促进脂质合成和谷氨酰胺代谢重编程。谷氨酰胺介导的营养信号能够通过m TORC1依赖性磷酸化激活SRC-2,进而通过共激活SREBP-1启动下游转录应答,增强与脂质合成相关的酶的表达。对人类前列腺癌进行代谢表达谱分析发现,与原位肿瘤细胞相比,发生转移的肿瘤细胞SRC-2驱动的代谢基因表达水平更高,进一步提示SRC-2作为代谢调节因子在肿瘤细胞转移过程中发挥重要作用。除此之外,在小鼠模型中抑制SRC-2能够显著抑制前列腺癌细胞的存活,生长和转移。
 
总的来说,这些结果表明SRC-2信号途径可能是治疗前列腺癌的有效靶点。(生物谷Bioon.com)
 
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Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis
 
Subhamoy Dasgupta1, Nagireddy Putluri1, Weiwen Long1, Bin Zhang1, Jianghua Wang2,Akash K. Kaushik1, James M. Arnold1, Salil K. Bhowmik1, Erin Stashi1, Christine A. Brennan3,Kimal Rajapakshe1, Cristian Coarfa1, Nicholas Mitsiades1, Michael M. Ittmann2,4,Arul M. Chinnaiyan3,5,6, Arun Sreekumar1 and Bert W. O'Malley1
 
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.
 
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