Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA152

Poster Communications

Sphingolipid Signals Regulate Hypoxia-Inducible Factors in Macrophages and Fibroblasts

U. G. Glaser1, A. Haimovitz-Friedman2, J. Fandrey1

1. Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Essen, Germany. 2. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States.

Tumor hypoxia impairs efficacy of radiotherapy. Within hypoxic areas gene expression is controlled and mediated by the transcription factor complex hypoxia-inducible factor 1 (HIF-1). Additionally, the sphingolipid metabolism becomes increasingly recognized as target for cancer treatment. Preliminary data indicate interplay between sphingolipid signaling and HIF-1 activation. Acid sphingomyelinase (Asm), which hydrolyses sphingomyelin to ceramide, has recently been recognized to significantly impact tumor sensitivity to radiation therapy (1). In this context, Asm activation is required to induce endothelial damage after high single dose radiation therapy (SDRT). Here, we investigated the molecular mechanisms that control HIF-1α subunit expression by sphingolipids in different cell types with special regard to the Asm/ceramide system. Both, fibroblasts and macrophages are highly represented cell types in the tumor microenvironment. Induction of ceramide caused by treatment with compound C, an inducer of ceramide synthase, increased the expression of HIF-1α in monocytic PLB and THP-1 cells under normoxia and hypoxia. Asm-deficient mouse embryonic fibroblasts (MEFs) treated with hypoxia and toll-like receptor 4 ligands show elevated HIF-1α accumulation compared with wild type cells. An increase of HIF-1α protein and mRNA expression was detected in MEFs coincident with increased levels of sphingosine-1-phosphate. Our data thus far suggest interplay between lipid signaling and HIF-1 activation, and provide a basis for further in vivo studies on the function and regulation of the hypoxic response after SDRT.

Where applicable, experiments conform with Society ethical requirements