title: cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions.
abstract: 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.
authors: 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.
authors: Linchong
authors: L
authors: Sun
authors: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors: Libing
authors: L
authors: Song
authors: CAS Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors: Qianfen
authors: Q
authors: Wan
authors: 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.
authors: Gongwei
authors: G
authors: Wu
authors: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors: Xinghua
authors: X
authors: Li
authors: 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.
authors: Yinghui
authors: Y
authors: Wang
authors: CAS Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
authors: Jin
authors: J
authors: Wang
authors: 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.
authors: Zhaoji
authors: Z
authors: Liu
authors: 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.
authors: Xiuying
authors: X
authors: Zhong
authors: 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.
authors: Xiaoping
authors: X
authors: He
authors: 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.
authors: Shengqi
authors: S
authors: Shen
authors: State Key Laboratory of Proteomics, China National Center of Biomedical Analysis, Beijing 100850, China.
authors: Xin
authors: X
authors: Pan
authors: State Key Laboratory of Proteomics, China National Center of Biomedical Analysis, Beijing 100850, China.
authors: Ailing
authors: A
authors: Li
authors: 1] CAS Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors: Yulan
authors: Y
authors: Wang
authors: 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.
authors: Ping
authors: P
authors: Gao
authors: 1] CAS Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China [2] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200433, China.
authors: Huiru
authors: H
authors: Tang
authors: 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.
authors: Huafeng
authors: H
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D005508:Food Deprivation; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D012694:Serine / Q000096:biosynthesis / Q000235:genetics; D000637:Transaminases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012694:Serine; D000637:Transaminases; C022393:phosphoserine aminotransferase; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D005978:Glutathione