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Cancers
Volume 12
Issue 1
10.3390/cancers12010237
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Article

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

by
Lindsey R. Conroy
1,
Susan Dougherty
2,
Traci Kruer
2,†,
Stephanie Metcalf
1,‡,
Pawel Lorkiewicz
3,4,
Liqing He
4,
Xinmin Yin
4,
Xiang Zhang
4,
Sengodagounder Arumugam
2,
Lyndsay E.A. Young
5,
Ramon C. Sun
6,7 and
Brian F. Clem
1,2,*
1
Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA
2
James Graham Brown Cancer Center, Louisville, KY 40202, USA
3
Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Louisville, KY 40202, USA
4
Department of Chemistry, University of Louisville, Center for Regulatory and Environmental Analytical Metabolomics, Louisville, KY 40208, USA
5
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
6
Department of Neuroscience, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
7
Markey Cancer Center, Lexington, KY 40536, USA
*
Author to whom correspondence should be addressed.
†
Current address: Moffitt Cancer Center, Tampa, FL 33612, USA.
‡
Current address: Indiana University, Bloomington, IN 47405, USA.
Cancers 2020, 12(1), 237; https://doi.org/10.3390/cancers12010237
Received: 28 November 2019 / Revised: 30 December 2019 / Accepted: 14 January 2020 / Published: 17 January 2020
(This article belongs to the Collection Recent Advances in Tumor Suppressor)
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Abstract

Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors. View Full-Text
Keywords: Rb1; metabolomics; glycolysis; TCA anaplerosis; lung cancer Rb1; metabolomics; glycolysis; TCA anaplerosis; lung cancer
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MDPI and ACS Style

Conroy, L.R.; Dougherty, S.; Kruer, T.; Metcalf, S.; Lorkiewicz, P.; He, L.; Yin, X.; Zhang, X.; Arumugam, S.; Young, L.E.A.; Sun, R.C.; Clem, B.F. Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo. Cancers 2020, 12, 237. https://doi.org/10.3390/cancers12010237

AMA Style

Conroy LR, Dougherty S, Kruer T, Metcalf S, Lorkiewicz P, He L, Yin X, Zhang X, Arumugam S, Young LEA, Sun RC, Clem BF. Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo. Cancers. 2020; 12(1):237. https://doi.org/10.3390/cancers12010237

Chicago/Turabian Style

Conroy, Lindsey R., Susan Dougherty, Traci Kruer, Stephanie Metcalf, Pawel Lorkiewicz, Liqing He, Xinmin Yin, Xiang Zhang, Sengodagounder Arumugam, Lyndsay E.A. Young, Ramon C. Sun, and Brian F. Clem. 2020. "Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo" Cancers 12, no. 1: 237. https://doi.org/10.3390/cancers12010237

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