AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma.

Abstract

Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-023-00195-z.