Abstract 1271: Human non small cell lung cancer tissue has enhanced expression of pyruvate carboxylase, but not glutaminase

Abstract

Abstract Altered cellular metabolism in tumors is well established, particularly an increased rate of aerobic glycolysis [1]. However, increased glycolysis alone is insufficient to sustain the enhanced cell growth and anabolic metabolism characteristic of cancer. Another key source of these precursors is the citric acid cycle (CAC). Removal of CAC intermediates for anabolism requires replenishment by other sources; these anaplerotic reactions are vital to cancer development. The two major pathways of anaplerosis are glutaminolyis (deamidation and transamination of glutamine to 2-oxoglutarate) [2] and carboxylation of pyruvate to oxaloacetate (OAA), catalyzed by pyruvate carboxylase (PCB) [2]. We have coupled 13C-labeled glucose tracer with stable isotope resolved metabolomics (SIRM), gene microarray, and western blotting to track the anaplerotic PCB pathway in human lung cancer patients. The resected cancer tissue showed increased flux through the PCB pathway, along with increased transcription of the PCB gene and PCB protein expression compared with the adjacent benign lung tissue [3]. We have extended these findings to 50 paired tissue samples, and have correlated them with histological and clinical data. The protein expression of PCB was on average ten-fold higher in the tumor than in the benign lung tissue (p=0.00001, paired t-test). The normalized protein expression correlated with the fraction of the tumor that was identified as cancer cells, indicating that the increased expression was from the cancer cells rather than other lung cell types. Glutaminase was active in the lung tissue, but its expression was not different from, or lower in the tumors than in the benign lung tissue. These data indicate that in NSCLC, PCB is important in anaplerosis and tumor metabolism. The balance between glycolysis and the choice of different anaplerotic pathways may depend on the tissue types.