NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells.

Abstract

Glioblastoma (GBM) is the most aggressive and common glioma subtype with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy, thus more effective approaches are needed. The glioblastoma tumoral mass is characterized by a small cellular subpopulation, the Glioblastoma stem cells (GSCs), which has been held accountant for initiation, invasion, proliferation, relapse and resistance to chemo- and radiotherapy. Targeted therapies against GSCs are crucial, and so is the understanding of the molecular mechanisms that govern the GSCs. Transforming growth factor {beta} (TGF{beta}), platelet growth factor (PDGF) signalling and Reactive Oxygen Species (ROS) production govern and regulate cancer-stem cell biology. In this work, we focus on the role of the NADPH oxidase 4 (NOX4) downstream of TGF{beta} signalling in the GSCs. NOX4 utilises NADPH to generate ROS; TGF{beta} induces NOX4 expression, thus increasing ROS production. Interestingly, NOX4 itself regulates GSC self-renewal and modulates Since TGF{beta} regulates PDGFB in GSC, we analysed how PDGFB modulates NOX4 expression and increases ROS production. Both TGF{beta} and PDGF signalling regulate GSC proliferation in a NOX4/ROS-dependent manner. The transcription factor NRF2, involved in the transcriptional regulation of antioxidant and metabolic responses, is regulated by both TGF{beta} and NOX4. This results in an antioxidant response, which positively contributes to GSC self-renewal and proliferation. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.