Loss of the Retinoblastoma Protein Modulates Glucose Metabolism in Lung Cancer

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 (Rb) is a tumor suppressor that was initially characterized in regulating cell cycle progression but recent studies have highlighted a functional role for Rb in controlling cellular metabolism. As such, we aim to characterize the metabolic phenotype caused by genetic loss of Rb in a mouse model of lung cancer. We have employed the Kras+/LSLG12D/Rb1lox/lox and Kras+/LSLG12D/Rb1+/+ transgenic model to study the metabolic effects of Rb1 loss in lung cancer. Cre‐exposed Kras+/LSLG12D/Rb1lox/lox mice exhibit increased tumor burden as well as decreased overall survival compared to Kras+/LSLG12D/Rb1+/+ mice. Our tracer studies using bolus dosing of 13C‐glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1 depleted tumors expressed higher hexokinase 2 and glucose transporter 1. Additionally, compared to Rb1‐proficient tumors, Rb1 null tumors exhibit decreased one and three carbon labeled aspartate, which is indicative of pyruvate carboxylase (PC) activity. However, Rb1−/− tumors were found to express higher PC compared to Rb1+/+ tumors, suggesting these tumors may utilize an alternative nutrient source for TCA anaplerosis other than glucose. Taken together, these data have identified several metabolic genes under Rb control, and suggest Rb may regulate differential nutrient utilization in lung tumors.Support or Funding InformationNCI RO1CA166327, American Cancer Society RSG 13‐139‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.