(176e) Metabolic Rewiring Induced By Hyperactive Akt Signaling in Cancer Cells

Metabolic Rewiring Induced by Hyperactive Akt Signaling in Cancer Cells

At a molecular level, cancer is a disease of deregulated cell growth arising from genetic mutations that result in improper cell signaling. A key enzyme in mediating cellular growth response is the Akt serine/threonine kinase. This enzyme mediates a host of proliferative and survival responses including advancing cell cycle progression, increasing rate of biosynthesis, and increasing apoptotic resistance. Hyperactivation of the Akt signaling axis is implicated in a number of cancers including prostate, breast, lung, and colon cancers. Akt is also known to exhibit profound regulation of central carbon metabolism at the transcriptional, translational, post-translational, and allosteric levels. Our group has employed metabolic flux analysis using isotopically labeled glucose to map the flow of carbon through central metabolic processes in both a wild-type pro-B-cell line and a derivative line expressing constitutively active myr-Akt. Through comparison of flux maps generated for these cell lines, we have discovered significant metabolic reprogramming in multiple central carbon pathways as a result of Akt signaling.

Prior biochemical studies of Akt have shown that its activation leads to increased expression of glycolytic enzymes including the GLUT1 glucose transporter and hexokinase, two rate-limiting enzymes in glycolysis. Consistent with these previous results, we show that constitutive Akt signaling leads to a 3-fold increase in glucose uptake and a 5-fold increase in lactate secretion. Interestingly, we show that Akt activity also has profound effects on amino acid utilization. Although extracellular exchange rates for the amino acids glycine and serine are similar, Akt is shown to rewire cells' intracellular utilization as evidenced through increased labeling enrichment of serine in cells with hyperactive Akt and through direct comparison of flux maps. Abnormalities in glycine and serine utilization have recently been linked to more aggressive, cancerous phenotypes in other cell lines. Our results also show changes in pentose phosphate activity with wild-type cells failing to send carbon through the oxidative branch, imposing interesting constraints on NADPH production that are quantified in the metabolic flux analyses. Full characterization of the metabolic changes induced by Akt to support proliferation and survival of cancer cells will lead to better therapeutic and adjuvant treatments for the host of cancer subtypes with aberrant Akt signaling.