Interplay between hypoxia-inducible factors and apoptosis in glioblastoma

Glioblastoma (GBM), the most common primary brain malignancy, is characterized by a highly hypoxic tumor microenvironment. Hypoxia stabilizes the transcription factors HIF-1α and HIF-2α, which promote tumor progression and treatment resistance by mediating important adaptive responses, such as angiogenesis, metabolic reprogramming, and apoptosis resistance. Hypoxia has also been shown to promote apoptosis resistance by HIF-mediated inhibition of pro-apoptotic signaling (e.g., p53) and induction of anti-apoptotic proteins (e.g., Bcl-2 and Bcl-xL). Furthermore, HIF-2α is known to maintain glioblastoma stem-like cells (GSCs), which can contribute to treatment resistance and intratumoral heterogeneity. Thus, the HIF–apoptosis axis has significant clinical implications for GBM, and small-molecule inhibitors of HIFs, as well as BH3 mimetics, are being investigated as potential therapeutic agents to reverse apoptosis resistance. Therefore, a combination of drugs targeting hypoxia signaling and apoptosis regulators could represent a promising therapeutic approach for overcoming GBM treatment resistance. In this review, we summarize recent advances in our understanding of the HIF–apoptosis axis in GBM and discuss potential therapeutic strategies that target this molecular crosstalk.