Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells

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• 作者：Anne Le¹ ; ^{annele@jhmi.edu} ; Andrew  ; N. Lane⁶ ; ⁸ ; ^{anlane01@louisville.edu} ; Max Hamaker² ; Sminu Bose¹ ; Arvin Gouw³ ; Joseph Barbi⁴ ; Takashi Tsukamoto⁵ ; Camilio  ; J. Rojas⁵ ; Barbara  ; S. Slusher⁵ ; Haixia Zhang⁹ ; Lisa  ; J. Zimmerman⁹ ; Daniel  ; C. Liebler⁹ ; Robbert  ; J.C. Slebos⁹ ; Pawel  ; K. Lorkiewicz⁶ ; Richard  ; M. Higashi⁶ ; ⁷ ; Teresa  ; W.M. Fan⁶ ; ⁷ ; ⁸ ; ^{twmfan@gmail.com} ; Chi  ; V. Dang¹⁰ ; ^{dangvchi@exchange.upenn.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 出版时间：4 January 2012
• 年：2012
• 卷：15
• 期：1
• 页码：110-121
• 全文大小：1829 K

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Summary

Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-¹³C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-¹³C,¹⁵N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their ¹³C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.