OncoTargets and Therapy (Oct 2018)
TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways
Abstract
Changyu Lu, Xiaolei Chen, Qun Wang, Xinghua Xu, Bainan Xu Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China Background and objective: The present study was designed to explore the roles of mitochondrial fission and MAPK–ERK–YAP signaling pathways and to determine their mutual relationship in TNFα-mediated glioblastoma mitochondrial apoptosis.Materials and methods: Cellular viability was measured via TUNEL staining, MTT assays, and Western blot. Immunofluorescence was performed to observe mitochondrial fission. YAP overexpression assays were conducted to observe the regulatory mechanisms of MAPK–ERK–YAP signaling pathways in mitochondrial fission and glioblastoma mitochondrial apoptosis.Results: The results in our present study indicated that TNFα treatment dose dependently increased the apoptotic rate of glioblastoma cells. Functional studies confirmed that TNFα-induced glioblastoma apoptosis was attributable to increased mitochondrial fission. Excessive mitochondrial fission promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, repressed ATP metabolism, elevated ROS synthesis, and downregulated antioxidant factors. In addition, the fragmented mitochondria liberated cyt-c into the cytoplasm/nucleus where it activated a caspase-9-involved mitochondrial apoptosis pathway. Furthermore, our data identified MAPK–ERK–YAP signaling pathways as the primary molecular mechanisms by which TNFα modulated mitochondrial fission and glioblastoma apoptosis. Reactivation of MAPK–ERK–YAP signaling pathways via overexpression of YAP neutralized the cytotoxicity of TNFα, attenuated mitochondrial fission, and favored glioblastoma cell survival.Conclusion: Overall, our data highlight that TNFα-mediated glioblastoma apoptosis stems from increased mitochondrial fission and inactive MAPK–ERK–YAP signaling pathways, which provide potential targets for new therapies against glioblastoma. Keywords: glioblastoma, apoptosis, mitochondrion, TNFα, mitochondrial fission, MAPK-ERK-YAP signaling pathways
