PO-131 Reprogramming of cancer cell metabolism by adaptation to chronic cycling severe hypoxia increases radiation resistance

Abstract

ABSTRACT Introduction Hypoxia-mediated resistance of solid tumours to ionising radiation is a major obstacle to successful radiotherapy. We showed previously that chronic cycling hypoxia drives the evolution of anoxia/reoxygenation-tolerant (ART) cancer cells with increased resistance to ionising radiation. Radiation resistance of ART cancer cells was associated with complex metabolic reprogramming, Matschke et al., Antioxid Redox Signal 201625:89–107; Matschke et al., Radiat Oncol 201611(1:75). Aim of the present study was to gain a more comprehensive understanding of the metabolic adaptation of cancer cells and to systematically explore opportunities for targeted pharmacologic intervention based on their suspected specific metabolic needs upon irradiation. Material and methods We compared gene expression profiles of ART and control cancer cells by microarray analysis and validated genes of interest by qRT-PCR. We used LC-MS high-throughput metabolomics, metabolic flux analyses, nutrient deprivation and drugs interfering with metabolism to characterise the cellular metabolic state without/with irradiation. Results and discussions Our microarray data indicated changes in major metabolic pathways after chronic cycling hypoxia selection. Furthermore, tolerance to severe hypoxia was associated with the formation of enlarged mitochondria in ART NCI-H460 cells. The analysis of metabolic alterations in irradiated cancer cells by LC-MS high-throughput metabolome analysis demonstrated a high and time-dependent need of irradiated cancer cells in central metabolism. Targeting of induced metabolic alterations disturbed redox homeostasis, altered mitochondrial metabolism and sensitised cancer cells to ionising radiation. Conclusion Specific metabolic requirements under stress conditions such as severe hypoxia or irradiation render cancer cells vulnerable to metabolic inhibitors alone and in combination with ionising radiation in a context and cell type-dependent manner. Supported by grants of the DFG (GRK1739/2) and the Deutsche Krebshilfe (1 10 355 and 70112711).