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

International Journal of Oncology
Seung Hee YooYoung Hyun Yoo

Abstract

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.

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Citations

Oct 16, 2015·Molecular Medicine Reports·Byoungduck ParkKwang-Hoon Chun
May 27, 2020·Journal of Cellular Physiology·Masoud Nouri-VaskehBehzad Baradaran

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