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: Linchong Sun, Libing Song, Qianfen Wan, Gongwei Wu, Xinghua Li, Yinghui Wang, Jin Wang, Zhaoji Liu, Xiuying Zhong, Xiaoping He, Shengqi Shen, Xin Pan, Ailing Li, Yulan Wang, Ping Gao, Huiru Tang, Huafeng Zhang
• Journal: Cell research (Cell Res) Vol. 25 Issue 4 Pg. 429-44 (Apr 2015) ISSN: 1748-7838 [Electronic] England
• PMID: 25793315 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-myc
• Serine
• Transaminases
• phosphoserine aminotransferase
• Phosphoric Monoester Hydrolases
• phosphoserine phosphatase
• Glutathione

Topics

• Animals
• Apoptosis (genetics)
• Carcinoma, Hepatocellular (enzymology, metabolism, pathology)
• Cell Proliferation (genetics)
• Food Deprivation
• Gene Expression Regulation, Neoplastic
• Glutathione (biosynthesis)
• Humans
• Liver Neoplasms (enzymology, metabolism, pathology)
• Metabolic Networks and Pathways (genetics)
• Mice
• Phosphoric Monoester Hydrolases (biosynthesis, genetics)
• Proto-Oncogene Proteins c-myc (biosynthesis, genetics)
• Serine (biosynthesis, genetics)
• Transaminases (biosynthesis, genetics)