Abstract 5401: Proliferation-independent regulation of tumor glycolysis by platelet-derived growth factor-mediated activation of AKT.
Authors: Cong Ran, Huan Liu, Mark A. Israel
Journal: Cancer Research (2013)

Abstract The difference in glucose metabolism between malignant and normal tissues has called attention to the importance of understanding the molecular mechanisms by which tumor metabolism is regulated. Inhibition of tyrosine kinase receptor (RTK) has been demonstrated as an effective strategy to target tumor growth, but whether RTKs can directly regulate glucose metabolism independent of its role in proliferation is not known. To explore the relationship between RTK function, glucose metabolism and proliferation, we developed primary cell cultures enriched for stem and progenitor populations from our mouse glioma model in which doxycycline inhibition of PDGF expression abolished tumor cell proliferation. We observed in primary glioma-derived tumor stem-like cells (TSCs) changes consistent with the Warburg Effect: enhanced glycolysis compared to the levels observed in normal neural stem cells (NSCs) determined by increased glucose consumption, lactate production, glycolytic rate, and intracellular ATP. We further differentiated glycolysis from mitochondrial activity as the source of increased intracellular ATP, as we observed a yet greater difference in intracellular ATP between NSCs and TSCs when they were exposed to uncoupling agents to inhibit oxidative phosphorylation. Modulation of PDGF expression by doxycycline indicated that PDGF was required to maintain enhanced glycolysis in glioma-derived TSCs. We additionally demonstrated that PDGF expression is strongly associated with the mRNA expression of regulatory enzymes in glycolytic pathway, indicating a possibility of direct regulation of glycolysis by PDGF signaling. To determine whether PDGF regulates glioma glycolysis by altering cellular proliferation, we first cell-cycle arrested TSCs and examined the effect of PDGF modulation on glycolysis. We found that loss of PDGF expression significantly reduced lactate production and glucose consumption, despite cell-cycle arrest. To further dissect whether PDGF directly regulates glycolysis independent of proliferation, we modulated levels of PDGF signaling in TSCs derived from doxycycline-resistant gliomas. In these TSCs, doxycycline regulated segments of PDGF signaling but no longer modified tumor cell proliferation, although glycolysis remained sensitive to modulation by PDGF signaling. These findings indicated that PDGF modulated glycolysis was independent of the well-described regulatory pathways that mediate the regulation of proliferation. We next determined that AKT, a known regulator of tumor glycolysis, mediated the metabolic effects of PDGF. These findings demonstrate that RTK can directly modulate glycolysis in glioma, which rely on glucose metabolism for energy. PDGFR inhibition can be used as strategy to modulate glioma glucose metabolism in the setting of other anti-proliferative strategies. Citation Format: Cong Ran, Huan Liu, Mark A. Israel. Proliferation-independent regulation of tumor glycolysis by platelet-derived growth factor-mediated activation of AKT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5401. doi:10.1158/1538-7445.AM2013-5401 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.