Sun Linchong, Song Libing, Wan Qianfen, Wu Gongwei, Li Xinghua, Wang Yinghui, Wang Jin, Liu Zhaoji, Zhong Xiuying, He Xiaoping, Shen Shengqi, Pan Xin, Li Ailing, Wang Yulan, Gao Ping, Tang Huiru, Zhang Huafeng
CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China.
State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Cell Res. 2015 Apr;25(4):429-44. doi: 10.1038/cr.2015.33. Epub 2015 Mar 20.
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.
已知癌细胞会经历代谢重编程以维持生存和快速增殖，然而，致癌性病变如何在各种应激条件下协调代谢转换仍有待充分阐明。在此，我们表明，剥夺癌细胞的两种主要营养来源葡萄糖或谷氨酰胺，会显著激活丝氨酸生物合成途径（SSP），同时伴随着cMyc表达的升高。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激活。此外，我们证明，由cMyc促进的SSP激活导致谷胱甘肽（GSH）产量增加、细胞周期进程和核酸合成，这些对于细胞存活和增殖至关重要，尤其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）作为SSP途径的最终限速酶，在体外和体内对cMyc驱动的癌症进展都至关重要，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激活与癌症发展之间可能存在因果关系。综上所述，我们的结果表明，cMyc的异常表达导致SSP激活增强，这是代谢转换的一个重要部分，以促进营养缺乏条件下的癌症进展。
