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.

Nutrient stress revamps cancer cell metabolism

“…These results confirm previous data in colon cancer cells demonstrating that glucose deprivation promotes cell death unless they are deficient in the atypical PKC, PKCζ, and thus they can synthesize serine and glycine from glutamine through a process of "reverse glycolysis" [4]. Interestingly, Sun et al [3] extended these observations and made the important finding that the SSP pathway is activated not only under glucose deprivation condition [4] but also when cells are deprived of glutamine. These observations begged the question, why is the SSP pathway so relevant?…”

“…Therefore, the crosstalk between PHGDH and PKM2 appears central to the regulation of cancer metabolism. The results of Sun et al [3] showing that c-Myc stimulated SSP activation by transcriptionally regulating the expression of several SSP enzymes in cancer cells adds another very interesting layer of complexity to the regulation of the pathway. However, much work remains to be done to fully understand this complex regulatory cascades and their relevance in cancer metabolism.…”

“…In this regard, the work of Sun and co-workers show that when cancer cells are deprived of glucose or glutamine, the serine biosynthesis pathway (SSP) is activated [3] (Figure 1). These results confirm previous data in colon cancer cells demonstrating that glucose deprivation promotes cell death unless they are deficient in the atypical PKC, PKCζ, and thus they can synthesize serine and glycine from glutamine through a process of "reverse glycolysis" [4].…”

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

“…We have uncovered cMyc-mediated activation of serine synthesis pathway when glucose or glutamine is deprived [18] and HIF-1-mediated suppression of fatty acid β-oxidation when oxygen is scarce [16]. Further screening for changes of lipid metabolism-related genes led us to a surprising observation that a major enzyme for ketolysis, OXCT1, is dramatically induced in nutrition-deprived HCC cells.…”

“…Recently, we investigated the metabolic adaptation of human hepatocellular carcinoma (HCC) cells under various stress conditions [16][17][18]. We have uncovered cMyc-mediated activation of serine synthesis pathway when glucose or glutamine is deprived [18] and HIF-1-mediated suppression of fatty acid β-oxidation when oxygen is scarce [16].…”