Targeted inhibition of mitochondrial Hsp90 induces mitochondrial elongation in Hep3B hepatocellular carcinoma cells undergoing apoptosis by increasing the ROS level.
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.
Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
Seung Hee
SH
Yoo
Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
Hye Young
HY
Kim
Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
Jee Hyun
JH
Rho
Department of Medical Genetics, School of Medicine, Ajou University, Suwon, Republic of Korea.
Seon-Yong
SY
Jeong
Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
Jeanho
J
Yun
Department of Dental Pharmacology and Biophysics, School of Dentistry and Research Institute for Oral Biotechnology, Yangsan Campus of Pusan National University, Yangsan, Republic of Korea.
Il
I
Yun
Department of Physiology and Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan, Republic of Korea.
Hwan Tae
HT
Park
Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
Young Hyun
YH
Yoo
D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006146:Guanidines / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*
D056744:Cyclin B1; D006146:Guanidines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D033681:Mitochondrial Membrane Transport Proteins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C557898:gamitrinib-G4; C521096:triphenylphosphonium methylide; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C470017:Mfn1 protein, human