Targeted inhibition of mitochondrial Hsp90 induces mitochondrial elongation in Hep3B hepatocellular carcinoma cells undergoing apoptosis by increasing the ROS level

摘要

Previous studies reported that a Gamitrinib variant containing triphenylphosphonium (G-TPP) binds to mitochondrial Hsp90 and rapidly inhibits its activity to induce apoptosis. We investigated the mechanisms underlying the antitumor activity of G-TPP in Hep3B hepatocellular carcinoma cells. Contrary to our predictions, we observed mitochondrial elongation in the G-TPP-treated Hep3B?cells undergoing apoptosis. We found that the G-TPP-induced mitochondrial elongation in Hep3B?cells was caused by a decrease in the mitochondrial fission-regulating protein Drp1 rather than by changes in the mitochondrial fusion machinery proteins Mfn1 and Opa1. Furthermore, G-TPP induced G2-M?phase cell cycle arrest by reducing the interaction between CDK1 and cyclin?B1. Additionally, reactive oxygen species (ROS) played a pivotal role in G-TPP-induced cell death and mitochondrial elongation in Hep3B?cells, and these processes are mediated by the reduced association of CDK1 with cyclin?B1 and the suppressed phosphorylation of Drp1 (Ser616). Thus, G-TPP induces cell death and causes Drp1-mediated mitochondrial elongation in Hep3B?cells by increasing the ROS level.