Loss of <i>Rb1</i> Enhances Glycolytic Metabolism in <i>Kras</i>-Driven Lung Tumors In Vivo

• Main Authors: Lindsey R. Conroy, Susan Dougherty, Traci Kruer, Stephanie Metcalf, Pawel Lorkiewicz, Liqing He, Xinmin Yin, Xiang Zhang, Sengodagounder Arumugam, Lyndsay E.A. Young, Ramon C. Sun, Brian F. Clem
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Cancers
• Subjects: <i>rb1</i>; metabolomics; glycolysis; tca anaplerosis; lung cancer
• Online Access: https://www.mdpi.com/2072-6694/12/1/237

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 (<i>Rb1</i>) in a transgenic mutant <i>Kras</i>-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, <i>Rb1</i>-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of <i>Rb1</i> did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact <i>Rb1</i>. Additional tracer studies using [U-¹³C,¹⁵N]-glutamine and [U-¹³C]-lactate demonstrated that loss of <i>Rb1</i> 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 <i>Rb1</i> promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in <i>Kras</i>-driven lung tumors.