Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

Emma E. Vincent; Alexey Sergushichev; Takla Griss; Marie Claude Gingras; Bozena Samborska; Thierry Ntimbane; Paula P. Coelho; Julianna Blagih; Thomas C. Raissi; Luc Choinière; Gaëlle Bridon; Ekaterina Loginicheva; Breanna R. Flynn; Elaine C. Thomas; Jeremy M. Tavaré; Daina Avizonis; Arnim Pause; Douglas J E Elder; Maxim N. Artyomov; Russell G. Jones

doi:10.1016/j.molcel.2015.08.013

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

Emma E. Vincent, Alexey Sergushichev, Takla Griss, Marie Claude Gingras, Bozena Samborska, Thierry Ntimbane, Paula P. Coelho, Julianna Blagih, Thomas C. Raissi, Luc Choinière, Gaëlle Bridon, Ekaterina Loginicheva, Breanna R. Flynn, Elaine C. Thomas, Jeremy M. Tavaré, Daina Avizonis, Arnim Pause, Douglas J E Elder, Maxim N. Artyomov^*, Russell G. Jones

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

Original language	English
Pages (from-to)	195-207
Number of pages	13
Journal	Molecular Cell
Volume	60
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2015.08.013
Publication status	Published - 15 Oct 2015

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Date of Acceptance: 17/10/2015

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This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Cell Press at http://www.sciencedirect.com/science/article/pii/S1097276515006590. Please refer to any applicable terms of use of the publisher.
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Vincent, E. E., Sergushichev, A., Griss, T., Gingras, M. C., Samborska, B., Ntimbane, T., Coelho, P. P., Blagih, J., Raissi, T. C., Choinière, L., Bridon, G., Loginicheva, E., Flynn, B. R., Thomas, E. C., Tavaré, J. M., Avizonis, D., Pause, A., Elder, D. J. E., Artyomov, M. N., & Jones, R. G. (2015). Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth. Molecular Cell, 60(2), 195-207. https://doi.org/10.1016/j.molcel.2015.08.013

@article{7e24d67e0600421293d43bd1a2f4a636,

title = "Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth",

abstract = "Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.",

author = "Vincent, {Emma E.} and Alexey Sergushichev and Takla Griss and Gingras, {Marie Claude} and Bozena Samborska and Thierry Ntimbane and Coelho, {Paula P.} and Julianna Blagih and Raissi, {Thomas C.} and Luc Choini{\`e}re and Ga{\"e}lle Bridon and Ekaterina Loginicheva and Flynn, {Breanna R.} and Thomas, {Elaine C.} and Tavar{\'e}, {Jeremy M.} and Daina Avizonis and Arnim Pause and Elder, {Douglas J E} and Artyomov, {Maxim N.} and Jones, {Russell G.}",

note = "Date of Acceptance: 17/10/2015",

year = "2015",

month = oct,

day = "15",

doi = "10.1016/j.molcel.2015.08.013",

language = "English",

volume = "60",

pages = "195--207",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

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Vincent, EE, Sergushichev, A, Griss, T, Gingras, MC, Samborska, B, Ntimbane, T, Coelho, PP, Blagih, J, Raissi, TC, Choinière, L, Bridon, G, Loginicheva, E, Flynn, BR, Thomas, EC, Tavaré, JM, Avizonis, D, Pause, A, Elder, DJE, Artyomov, MN & Jones, RG 2015, 'Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth', Molecular Cell, vol. 60, no. 2, pp. 195-207. https://doi.org/10.1016/j.molcel.2015.08.013

TY - JOUR

T1 - Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

AU - Vincent, Emma E.

AU - Sergushichev, Alexey

AU - Griss, Takla

AU - Gingras, Marie Claude

AU - Samborska, Bozena

AU - Ntimbane, Thierry

AU - Coelho, Paula P.

AU - Blagih, Julianna

AU - Raissi, Thomas C.

AU - Choinière, Luc

AU - Bridon, Gaëlle

AU - Loginicheva, Ekaterina

AU - Flynn, Breanna R.

AU - Thomas, Elaine C.

AU - Tavaré, Jeremy M.

AU - Avizonis, Daina

AU - Pause, Arnim

AU - Elder, Douglas J E

AU - Artyomov, Maxim N.

AU - Jones, Russell G.

N1 - Date of Acceptance: 17/10/2015

PY - 2015/10/15

Y1 - 2015/10/15

N2 - Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

AB - Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

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U2 - 10.1016/j.molcel.2015.08.013

DO - 10.1016/j.molcel.2015.08.013

M3 - Article (Academic Journal)

C2 - 26474064

AN - SCOPUS:84944889945

SN - 1097-2765

VL - 60

SP - 195

EP - 207

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

Abstract

Bibliographical note

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Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

Abstract

Bibliographical note

UN SDGs

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