cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions
cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions
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cMyc介导的丝氨酸生物合成途径的激活对于营养缺乏条件下的癌症进展至关重要
DOI：
10.1038/cr.2015.33
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发表时间：
2015-04-01
期刊：
影响因子：
44.1
通讯作者：
Zhang, Huafeng
中科院分区：
文献类型：
--
作者：
Sun, Linchong;Song, Libing;Zhang, Huafeng
已知癌细胞经历代谢重编程以维持存活和快速增殖，然而，致癌病变如何在各种应激条件下协调代谢开关仍有待充分阐明。在这里，我们表明，剥夺葡萄糖或谷氨酰胺，两个主要的营养来源的癌细胞，显着激活丝氨酸生物合成途径（SSP），伴随着cMyc表达升高。我们进一步确定cMyc通过转录上调多种SSP酶的表达来刺激SSP活化。此外，我们证明了cMyc促进的SSP激活导致谷胱甘肽（GSH）产生升高，细胞周期进展和核酸合成，这对细胞存活和增殖至关重要，特别是在营养缺乏的条件下。我们进一步发现，磷酸丝氨酸磷酸酶（PSPH），SSP途径的最终限速酶，在体外和体内cMyc驱动的癌症进展是至关重要的，重要的是，PSPH的异常表达与肝细胞癌（HCC）患者的死亡率高度相关，这表明这种cMyc调节的酶，或一般的SSP激活，和癌症发展之间的潜在因果关系。总之，我们的研究结果表明，cMyc的异常表达导致增强的SSP激活，这是代谢开关的重要组成部分，以促进营养缺乏条件下的癌症进展。
Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.