The p75 neurotrophin receptor enhances HIF-dependent signaling in glioma

Abstract

Tumor hypoxia is associated with several features of aggressive glioma growth, including migration, invasion, and stemness. Most of the cellular adaptation to hypoxia is mediated by the hypoxia-inducible factors HIF-1α and HIF-2α, but regulation of these factors by both oxygen-dependent and -independent mechanisms in brain tumors is only partially understood. Here, we show that the p75 neurotrophin receptor (p75^NTR) is stabilized at hypoxia in murine glioma in vivo, as well as in primary human glioma cultures in vitro. Expression of p75^NTR resulted in increased stabilization of HIF-1α and HIF-2α, and RNAi or pharmacologic targeting of p75^NTR diminished HIF stabilization and HIF-dependent signaling at hypoxia. Consequentially, p75^NTR inhibition resulted in decreased migration, invasion, and stemness in response to hypoxia, suggesting that p75^NTR is a central regulator of hypoxia-induced glioma aggressiveness. Together, our findings support the literature that identifies p75^NTR as a potential therapeutic target in brain tumors.

Keywords: Glioblastoma multiforme; HIF-1α; HIF-2α; Hypoxia; P75 neurotrophin receptor; Stemness.