Abstract 2128: PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival

BACKGROUND: Platelet-derived growth factor (PDGF) signaling plays a key role in gliomagenesis. Glioblastomas express all PDGF ligands and both cell membrane receptors, PDGFRα and PDGFRβ, that are involved in pro-survival autocrine and paracrine loops. Our previous work demonstrated that expression of PDGFRβ is enriched in hypoxic glioblastoma tumor tissues. Also, induction of mitophagy is a well-known critical coping response to tissue hypoxia. We therefore investigated the role of PDGFRβ signaling cascade in regulating hypoxia-induced mitophagy of glioblastoma. METHODS: Protein detection was performed by immunoblotting and immunofluorescence to determine changes in levels of target proteins upon RNA interference, treatment with PDGFRβ inhibitor, and ectopic gene transfection. MitoSox assay was used to measure mitochondrial reactive oxygen species (ROS). Tumor growth assays were performed in vitro and in vivo using subcutaneous tumor implantation model. RESULTS: PDGFRβ signaling was essential for induction of hypoxia-mediated mitophagy in glioblastoma cells. Nix, a hypoxic responsive protein and regulator of mitophagy, was necessary for PDGFRβ-mediated glioblastoma survival. Inhibition of PDGFRβ signaling pathway killed glioblastoma cells by suppressing mitophagy and leading to subsequent elevation of mitochondrial ROS. Furthermore, interference of mitophagic response by blocking PDGFRβ signaling enhanced cell death even in chemotherapy-resistant tumor cells. CONCLUSION: This work suggests a potential mechanism by which PDGFRβ inhibition could kill glioblastoma cells through suppression of NIX-mediated mitophagy. Manipulation of NIX and PDGFRβ pathway may provide novel therapeutic opportunities in chemoresistant tumor models. Citation Format: Jinkyu Jung, Mark R. Gilbert, Deric M. Park. PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2128. doi:10.1158/1538-7445.AM2017-2128