Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism

Abstract

Cancer cells can use a variety of metabolic substrates to fulfill the bioenergetic and biosynthetic needs of their oncogenic program. Besides bioenergetics, cancer cell metabolism also directly influences genetic, epigenetic and signaling events associated with tumor progression. Many cancer cells are addicted to glutamine, and this addiction is observed in oxidative as well as in glycolytic cells. While both oxidative and bioreductive glutamine metabolism can contribute to cancer progression and glutamine can further serve to generate peptides (including glutathione) and proteins, we report that glutamine promotes the proliferation of cancer cells independently of its use as a metabolic fuel or as a precursor of glutathione. Extracellular glutamine activates transcription factor STAT3, which is necessary and sufficient to mediate the proliferative effects of glutamine in glycolytic and in oxidative cancer cells. Glutamine also activates transcription factors HIF-1, mTOR and c-Myc, but these factors do not mediate the effects of glutamine on cancer cell proliferation. Our findings shed a new light on the anticancer effects of L-asparaginase that possesses glutaminase activity and converts glutamine into glutamate extracellularly. Conversely, cancer resistance to treatments that block glutamine metabolism could arise from glutamine-independent STAT3 re-activation.

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

“…It has recently been shown that glutamine per se activates STAT3, which promotes cancer cell proliferation, and that STAT3 activation is independent of glutamine metabolism. 50 This is not inconsistent with our results, which show that HJC0152 regulates not only STAT3, but also metabolites including glutamine in NSCLC cells.…”

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

“…As an example, extracellular glutamine was recently shown to activate the transcription factor STAT3 to promote cancer cell proliferation [64]. Intracellular glutamine as well can stimulate cell signaling pathways, indirectly activating the mechanistic target of rapamycin complex 1 (mTORC1) [65].…”

Plasma cells: You are what you eat

“…Furthermore, glycolysis can activate MCL1, an anti-apoptotic factor promoting myeloma survival. 213 Glutamine also can upregulate HIF1α and can possibly mediate survival of the tumor cell under conditions of hypoxia, a condition typically associated with the MM bone marrow. GLUT1 and GLUT6 are the chief glucose transporters in primary and MM murine cell lines, but human MM lines show elevated levels of the glucose transporters GLUT4, GLUT8, and GLUT11 with minimal expression of GLUT1.…”

“…210 Despite the importance of glucose in the metabolism of MM cells, the transporter responsible for its uptake is inconsistent between human and mouse cell lines. 213 In human MM cell lines, glutamine was preferentially shuttled through the tricarboxylic acid cycle as compared to glucose, and led to the synthesis of the oncometabolite 4-hydroxyglutarate. 105,210 The importance of glutamine in plasma cell metabolism was drawn from studies carried out in MM cell lines.…”