Marine-derived fungal metabolite MHO7 promotes glioblastoma cell apoptosis as a novel Akt inhibitor by targeting membrane phosphatidylethanolamine

Temozolomide (TMZ) chemoresistance is a major challenge in the management of glioblastoma (GBM). Marine-derived Fungal metabolites are a significant source of potential chemotherapeutic candidates. This study aimed to investigate the cytotoxic effect of MHO7 (6-epi-ophiobolin G) on GBM cells. MHO7 inhibited GBM cell proliferation and promoted Apoptosis, accompanied by a reduction in Akt activity and membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) content. We verified that MHO7 could react with phosphatidylethanolamine (PE), the second most abundant phospholipid in the plasma membrane, to form a covalent adduct. Pre-incubation with exogenous PE significantly alleviated the pro-apoptotic effect of MHO7, with a concomitant increase in Akt activity and membrane PIP2 and PIP3 content. Since binding to PIP3 is a key step in Akt activation, our results indicate that MHO7 can function as a novel Akt Inhibitor. Additionally, MHO7 has a synergistic pro-apoptotic effect with TMZ, and TMZ-resistant GBM cells remain sensitive to MHO7. MHO7 had little cytotoxicity against normal neuronal cells. The anti-growth effect of MHO7 was also observed in an orthotopic glioma mice model. Therefore, MHO7 is a promising chemotherapeutic agent for GBM. This study also indicated that membrane lipid-targeted therapy may be a novel and effective strategy for tumor treatment.

Akt; Chemoresistance; Glioblastoma; Ophiobolins; Phosphatidylethanolamine.