MAP17 Enhances Chemoresistance and Tumorigenicity of Glioblastoma-Initiating Cells via the Canonical NF-кB Pathway.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite multimodal treatments, including surgery, radiation therapy, and temozolomide (TMZ) chemotherapy, the median survival remains poor at approximately 15 months. One reason for the therapeutic resistance is the existence of GBM-initiating cells (GICs) within the tumor. Therefore, understanding the molecular insights of how GICs contribute to the therapy recurrence is crucial for developing new therapeutic strategies. Comparing expression profiles of TMZ-resistant GICs (GICRs) with those of GICs, we identified membrane-associated protein 17 (MAP17) as a new factor that is exclusively expressed in GICRs. We show that overexpression of MAP17 in GICs significantly increased their proliferation, TMZ resistance, and tumorigenicity, whereas its knockdown impaired these properties, indicating that MAP17 plays a critical role in both TMZ resistance and tumorigenicity of GICs. We also show that MAP17 increased the expression of anti-apoptotic protein BCL2 through the activation of RELA-dependent NF-κB pathway in GICs. Furthermore, we demonstrate that overexpression of BCL2 increased TMZ resistance in GICs and their tumorigenicity, while its knockdown deprived these malignant characters in GICRs. Taken together, these findings identify a novel signaling pathway, MAP17-NF-κB-BCL2, that controls TMZ resistance and tumorigenicity of GICs.