Abstract 2067: Tumor cell survival under microenvironmental stress: Hypoxia and/or low glucose upregulate poline oxidase

Abstract

Abstract Proline is a stress substrate which can be readily released from collagen in extracelluar matrix (ECM) initiated by matrix metalloproteinases accompanying tumor progression and invasion. Proline oxidase (POX) can metabolize proline to generate reactive oxygen species (ROS) for inducing apoptosis or autophagy; it also is a source of energy (ATP) under metabolic stress. However, the contribution of proline metabolism to tumorigenesis under concurrent hypoxia and low-glucose in the tumor microenvironment, has not been explored. In the present study, we showed that hypoxia and low glucose induced POX expression in HT29 colorectal cancer cells. The combination of low-glucose and hypoxia had additive effects on POX expression. Knockdown of HIF-1α, an important mediator of the hypoxic response, did not alter POX expression. Instead, inhibition of the activation of AMPK, the celluar energy sensor, by its antagonist (Compound C) blocked the upregulation of POX under conditions of either hypoxia or low glucose. Functional studies showed POX was consistently responsible for the maintenance of cell growth under hypoxia, low-glucose or with the combination of both. However, ATP and ROS assays showed that ATP production from POX was favored under low-glucose condition with or without hypoxia, whereas POX preferred ROS production with hypoxia. POX knockdown partially decreased hypoxia-induced prosurvival autophagy, which was also decreased by the antioxidant, N-acetylcysteine. Taken together, these results suggest that the induction of proline metabolism with hypoxia and/or low-glucose contributes an important mechanism by which tumor cells switch to a survival mode. These findings offer new insights into our understanding of energy metabolism in tumor cells beyond the well-recognized Warburg effect of aerobic glycolysis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2011-2067