Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells

Anne Le; Andrew N. Lane; Max Hamaker; Sminu Bose; Arvin Gouw; Joseph Barbi; Takashi Tsukamoto; Camilio J. Rojas; Barbara S. Slusher; Haixia Zhang; Lisa J. Zimmerman; Daniel C. Liebler; Robbert J.C. Slebos; Pawel K. Lorkiewicz; Richard M. Higashi; Teresa W.M. Fan; Chi V. Dang

doi:10.1016/j.cmet.2011.12.009

Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells

Anne Le, Andrew N. Lane, Max Hamaker, Sminu Bose, Arvin Gouw, Joseph Barbi, Takashi Tsukamoto, Camilio J. Rojas, Barbara S. Slusher, Haixia Zhang, Lisa J. Zimmerman, Daniel C. Liebler, Robbert J.C. Slebos, Pawel K. Lorkiewicz, Richard M. Higashi, Teresa W.M. Fan, Chi V. Dang

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Abstract

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.

Original language	English
Pages (from-to)	110-121
Number of pages	12
Journal	Cell Metabolism
Volume	15
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2011.12.009
State	Published - Jan 4 2012

Bibliographical note

Funding Information:
This work was supported by in part by grant 1R21NS074151-01 (to T.T.); The Sol Goldman Pancreatic Cancer Research fund (to A.L.); grants 5R01CA051497-21 and 5R01CA057341-20, Leukemia Lymphoma Society grant LLS-6363-11, and Stand-Up-to-Cancer/American Association for Cancer Research translational grant (to C.V.D.); grants 1R01CA118434-01A2 and 3R01CA118434-02S1, University of Louisville CTSPGP grants 20044 (to T.W.M.F.) and 20061 (to A.N.L.); and National Institutes of Health National Center for Research Resources (NIH NCRR) grant 5P20RR018733, Kentucky Challenge for Excellence, the Brown Foundation, and Kentucky Lung Cancer Research Program (postdoctoral fellowship to P.K.L.). The FT-ICR-MS instrumentation was supported by the National Science Foundation's Office of Experimental Program to Stimulate Competitive Research (NSF/EPSCoR) grant number EPS-0447479. We thank Ramani Dinavahi, Julie Tan, and Radhika Burra for excellent technical assistance and Stephen Rayport for the heterozygous glutaminase mice. A.L., A.N.L., T.W.M.F., and C.V.D. designed research and wrote the manuscript. A.L., A.N.L., M.H., S.B., J.B., C.J.R., H.Z., L.J.Z., R.J.C.S., P.K.L., R.M.H., and T.W.M.F. performed research; all authors interpreted the data and commented on the manuscript.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2011.12.009

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Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., Zimmerman, L. J., Liebler, D. C., Slebos, R. J. C., Lorkiewicz, P. K., Higashi, R. M., Fan, T. W. M., & Dang, C. V. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells. Cell Metabolism, 15(1), 110-121. https://doi.org/10.1016/j.cmet.2011.12.009

@article{26ff59c69c664ec1845877e545be169b,

title = "Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells",

abstract = "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.",

author = "Anne Le and Lane, {Andrew N.} and Max Hamaker and Sminu Bose and Arvin Gouw and Joseph Barbi and Takashi Tsukamoto and Rojas, {Camilio J.} and Slusher, {Barbara S.} and Haixia Zhang and Zimmerman, {Lisa J.} and Liebler, {Daniel C.} and Slebos, {Robbert J.C.} and Lorkiewicz, {Pawel K.} and Higashi, {Richard M.} and Fan, {Teresa W.M.} and Dang, {Chi V.}",

note = "Funding Information: This work was supported by in part by grant 1R21NS074151-01 (to T.T.); The Sol Goldman Pancreatic Cancer Research fund (to A.L.); grants 5R01CA051497-21 and 5R01CA057341-20, Leukemia Lymphoma Society grant LLS-6363-11, and Stand-Up-to-Cancer/American Association for Cancer Research translational grant (to C.V.D.); grants 1R01CA118434-01A2 and 3R01CA118434-02S1, University of Louisville CTSPGP grants 20044 (to T.W.M.F.) and 20061 (to A.N.L.); and National Institutes of Health National Center for Research Resources (NIH NCRR) grant 5P20RR018733, Kentucky Challenge for Excellence, the Brown Foundation, and Kentucky Lung Cancer Research Program (postdoctoral fellowship to P.K.L.). The FT-ICR-MS instrumentation was supported by the National Science Foundation's Office of Experimental Program to Stimulate Competitive Research (NSF/EPSCoR) grant number EPS-0447479. We thank Ramani Dinavahi, Julie Tan, and Radhika Burra for excellent technical assistance and Stephen Rayport for the heterozygous glutaminase mice. A.L., A.N.L., T.W.M.F., and C.V.D. designed research and wrote the manuscript. A.L., A.N.L., M.H., S.B., J.B., C.J.R., H.Z., L.J.Z., R.J.C.S., P.K.L., R.M.H., and T.W.M.F. performed research; all authors interpreted the data and commented on the manuscript. ",

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Le, A, Lane, AN, Hamaker, M, Bose, S, Gouw, A, Barbi, J, Tsukamoto, T, Rojas, CJ, Slusher, BS, Zhang, H, Zimmerman, LJ, Liebler, DC, Slebos, RJC, Lorkiewicz, PK, Higashi, RM , Fan, TWM & Dang, CV 2012, 'Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells', Cell Metabolism, vol. 15, no. 1, pp. 110-121. https://doi.org/10.1016/j.cmet.2011.12.009

TY - JOUR

T1 - Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells

AU - Le, Anne

AU - Lane, Andrew N.

AU - Hamaker, Max

AU - Bose, Sminu

AU - Gouw, Arvin

AU - Barbi, Joseph

AU - Tsukamoto, Takashi

AU - Rojas, Camilio J.

AU - Slusher, Barbara S.

AU - Zhang, Haixia

AU - Zimmerman, Lisa J.

AU - Liebler, Daniel C.

AU - Slebos, Robbert J.C.

AU - Lorkiewicz, Pawel K.

AU - Higashi, Richard M.

AU - Fan, Teresa W.M.

AU - Dang, Chi V.

N1 - Funding Information: This work was supported by in part by grant 1R21NS074151-01 (to T.T.); The Sol Goldman Pancreatic Cancer Research fund (to A.L.); grants 5R01CA051497-21 and 5R01CA057341-20, Leukemia Lymphoma Society grant LLS-6363-11, and Stand-Up-to-Cancer/American Association for Cancer Research translational grant (to C.V.D.); grants 1R01CA118434-01A2 and 3R01CA118434-02S1, University of Louisville CTSPGP grants 20044 (to T.W.M.F.) and 20061 (to A.N.L.); and National Institutes of Health National Center for Research Resources (NIH NCRR) grant 5P20RR018733, Kentucky Challenge for Excellence, the Brown Foundation, and Kentucky Lung Cancer Research Program (postdoctoral fellowship to P.K.L.). The FT-ICR-MS instrumentation was supported by the National Science Foundation's Office of Experimental Program to Stimulate Competitive Research (NSF/EPSCoR) grant number EPS-0447479. We thank Ramani Dinavahi, Julie Tan, and Radhika Burra for excellent technical assistance and Stephen Rayport for the heterozygous glutaminase mice. A.L., A.N.L., T.W.M.F., and C.V.D. designed research and wrote the manuscript. A.L., A.N.L., M.H., S.B., J.B., C.J.R., H.Z., L.J.Z., R.J.C.S., P.K.L., R.M.H., and T.W.M.F. performed research; all authors interpreted the data and commented on the manuscript.

PY - 2012/1/4

Y1 - 2012/1/4

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84855453655&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2011.12.009

DO - 10.1016/j.cmet.2011.12.009

M3 - Article

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AN - SCOPUS:84855453655

SN - 1550-4131

VL - 15

SP - 110

EP - 121

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -

Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in b cells

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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