Abstract
Glucose and Glutamine are two essential ingredients for cell growth. However, it remains open for investigation whether there is a general mechanism that coordinates the consumption of glucose and glutamine in cancer cells. Glutamine is mainly metabolized through the glutaminolysis pathway and our previous report indicated that CtBP increases GDH activity and promotes glutaminolysis through repressing the expression of SIRT4, a well-known mitochondrion-located factor that inhibits glutaminolysis pathway. CtBP is known to be a sensor of intracellular metabolic status; we thus hypothesized that a consensus CtBP-SIRT4-GDH axis may mediate the crosstalk between glycolysis and glutaminolysis. Herein, supporting this hypothesis, we observed the coordinated consumption of glucose and glutamine across different cell lines. This coordination was found to be related to CtBP repression activity on SIRT4 expression under high level of glucose but not low glucose level. Low level of glucose supply was found to decrease GDH activity via blocking CtBP dimerization. Mechanically, low glucose also abolished CtBP binding to SIRT4 promoter and the repression of SIRT4 expression. Consistently, the CtBP dimerization inhibitor MTOB mimicked low glucose effects on SIRT4 expression, and GDH activity suggest that CtBP requires high glucose supply to act as a suppressor of SIRT4 gene. In conclusion, we propose that a general molecular pathway composed by CtBP-SIRT4-GDH coordinating the metabolism of glucose and glutamine in cancer cells.
Highlights
Glucose and glutamine are critical nutrients indispensable for cancer cell growth[1]
In order to investigate whether glycolysis impacts glutaminolysis, we cultured MCF-7 cells in high glucose (HG, 4.5 g/L glucose) medium and low glucose (LG, 1 g/L glucose) medium but supplied with the same initial amount of glutamine (2 mM)
Our results showed that LG culture reduced CtBP binding at SIRT4 promoter significantly in MCF-7 and MDA-MB231 cells (Fig. 3d,e), suggesting there is a glucose metabolismrelated regulatory role of CtBP in repressing SIRT4 expression
Summary
Glucose and glutamine are critical nutrients indispensable for cancer cell growth[1]. Glucose is transported into cells and further metabolized to pyruvate through the glycolysis pathway. The pyruvate either enters the mitochondria for tricarboxylic acid (TCA) cycle, or it will be converted to lactate. The latter pathway represents a major advantage for cancer cell growth[4], even though some. The crosstalk between glycolysis and glutaminolysis has been noticed a long time ago; how these two processes influence each other is controversial. Pyruvate is the end product of glycolysis and glutamine can be used to produce pyruvate; the latter process is more complicated and needs
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