Induction of hypoxia-inducible factor-1α by BDNF protects retinoblastoma cells against chemotherapy-induced apoptosis

Alternations of environment signals such as neurotrophins may be the basis for malignant transformation of retinoblastoma (Rb), the most common primary intraocular malignancy in children. The aim of this study is to investigate the ability of brain-derived neurotrophic factor (BDNF) to decrease the chemosensitivity of Rb cells to the common chemotherapeutic agents and to explore the role of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in such cellular process. The results showed that BDNF could induce higher expression of HIF-1 alpha via activation of TrkB in human Y-79 retinoblastoma cells, which consequently contributed to its effect against chemotherapeutic agent-induced cytotoxicity and cell apoptosis. However, this protective effect could be potently reversed by knockdown of HIF-1 alpha. Furthermore, BDNF strikingly prevented chemotherapeutic agent-induced alternations of apoptosis-related molecules, which could also be attenuated by silencing HIF-1 alpha. Therefore, our findings demonstrated that BDNF could contribute to chemoresistance of Rb via modulation of HIF-1 alpha expression, indicating that targeting at the BDNF-TrkB/HIF-1 alpha signaling pathway might be a promising strategy for the treatment of retinoblastoma in the future.