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

Seung Hee Yoo; Hye Young Kim; Jee Hyun Rho; Seon-Yong Jeong; Jeanho Yun; Il Yun; Hwan Tae Park; Young Hyun Yoo

doi:10.3892/ijo.2015.3150

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

Int J Oncol. 2015 Nov;47(5):1783-92. doi: 10.3892/ijo.2015.3150. Epub 2015 Sep 7.

Authors

Seung Hee Yoo¹, Hye Young Kim¹, Jee Hyun Rho¹, Seon-Yong Jeong², Jeanho Yun³, Il Yun⁴, Hwan Tae Park⁵, Young Hyun Yoo¹

Affiliations

¹ Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
² Department of Medical Genetics, School of Medicine, Ajou University, Suwon, Republic of Korea.
³ Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
⁴ 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.
⁵ Department of Physiology and Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan, Republic of Korea.

PMID: 26351876
DOI: 10.3892/ijo.2015.3150

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
CDC2 Protein Kinase
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cyclin B1 / metabolism
Cyclin-Dependent Kinases / metabolism
GTP Phosphohydrolases / metabolism
Guanidines / therapeutic use
HSP90 Heat-Shock Proteins / genetics*
HSP90 Heat-Shock Proteins / metabolism
Humans
Lactams, Macrocyclic / therapeutic use
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
M Phase Cell Cycle Checkpoints / drug effects
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects
Mitochondria / genetics
Mitochondrial Dynamics / drug effects
Mitochondrial Dynamics / genetics
Mitochondrial Membrane Transport Proteins / metabolism
Organophosphorus Compounds / administration & dosage
Reactive Oxygen Species / metabolism*

Substances

Cyclin B1
Guanidines
HSP90 Heat-Shock Proteins
Lactams, Macrocyclic
Mitochondrial Membrane Transport Proteins
Organophosphorus Compounds
Reactive Oxygen Species
gamitrinib-G4
triphenylphosphonium methylide
CDC2 Protein Kinase
CDK1 protein, human
Cyclin-Dependent Kinases
GTP Phosphohydrolases
OPA1 protein, human
Mfn1 protein, human