Csig-36. Decreased Capicua (Cic) Enhances Oncogenic Etv4 Signaling in A mouse Model of Astrocytoma and Glioma Stem Cells

Abstract

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 PDGFRb 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 PDGFRb signaling cascade in regulating hypoxia-induced mitophagy of glioblastoma. PDGFRb signaling was essential for induction of hypoxiamediated mitophagy in glioblastoma cells. METHODS & RESULTS: Western blotting and immunofluorescence imaging with either RNA interference of PDGFRb or treatment with PDGFRb inhibitor showed that NIX, a hypoxic responsive protein and regulator of mitophagy, was necessary for PDGFRb-mediated glioblastoma survival under hypoxia. Detecting MitoSOX and MitoTracker Green along with treatment of PDGFRb inhibitor suggested that inhibition of PDGFRb signaling pathway led to accumulation of mitochondrial ROS, and subsequently killing glioblastoma cells by suppressing mitophagy. In tumor bearing mice model, PDGFRb inhibitor attenuated growth of tumor mass, however, ectopic NIX expression reversed such effect. Furthermore, interference of mitophagic response by blocking PDGFRβ signaling enhanced cell death even in temozolomideresistant tumor cells. CONCLUSIONS: This work suggests a potential mechanism by which PDGFRb inhibition could kill glioblastoma cells through suppression of NIX-mediated mitophagy. Manipulation of NIX and PDGFRb pathway may provide novel therapeutic opportunities in chemoresistant tumor models.