Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Yoo,Seung  Hee; Yoon,Young   Geol; Lee,Jee   Suk; Song,Yeon  Suk; Oh,Joon  Seok; Park,Bong  Soo; Kwon,Taeg  Kyu; Park,Cheol; Choi,Yung  Hyun; Yoo,Young  Hyun

doi:10.3892/ijo.2012.1585

Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Authors:
- Seung Hee Yoo
- Young Geol Yoon
- Jee Suk Lee
- Yeon Suk Song
- Joon Seok Oh
- Bong Soo Park
- Taeg Kyu Kwon
- Cheol Park
- Yung Hyun Choi
- Young Hyun Yoo
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Affiliations: Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea, College of Dentistry and Research Institute for Oral Biotechnology, Pusan National University, Busan, Republic of Korea, Department of Immunology, School of Medicine, Keimyung University, Taegu, Republic of Korea, Department of Biochemistry and Research Institute of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan, Republic of Korea
Published online on: August 7, 2012 https://doi.org/10.3892/ijo.2012.1585
Pages: 1443-1454

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Abstract

The Bcl-2 protein is known to exert not only anti-apoptotic but also anti-autophagic activities. Numerous studies have demonstrated that etoposide, which is one of the most widely used cancer chemotherapy agents, induces apoptotic cell death. However, the exact molecular mechanism leading to cell death by etoposide remains to be resolved. This study aimed to dissect the mode of cell death induced by etoposide in Hep3B hepatoma cells. Furthermore, this study was conducted to examine whether etoposide overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells. We observed that Hep3B cells treated with etoposide show not only apoptotic but autophagic phenotypes. Autophagy inhibition by 3-methyladenine (3MA) and caspase inhibition by zVAD-fmk effectively decreased autophagic and apoptotic phenotypes, respectively. However, either zVAD-fmk or 3MA only partially prevented cell death. These data indicate that etoposide concomitantly induces autophagic cell death and apoptosis in Hep3B cells. Importantly, etoposide can effectively induce cell death in Bcl-2-overexpressing Hep3B cells. Conversely, staurosporine, which exclusively induces apoptosis in Hep3B cells, did not efficiently induce cell death in Bcl‑2‑overexpressing Hep3B cells. Staurosporine-treated Hep3B cells also showed an autophagic phenotype. While autophagy is cell death-inducing in Hep3B cells treated with etoposide, it is cytoprotective in Hep3B cells treated with staurosporine. To this end, we observed that etoposide-induced mixed type of programmed cell death is associated with the dissociation of Bcl-2 from Beclin-1. Taken together, etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells.

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