title: Sorafenib overcomes the chemoresistance in HBx-expressing hepatocellular carcinoma cells through down-regulation of HBx protein stability and suppresses HBV gene expression.
abstract: Previous studies have revealed that HBx expression has anti-apoptotic effects, resulting in increased drug resistance in HCC cells. Thus, we examined if sorafenib efficiently induces apoptosis in HBx-overexpressing HCC cells. Noticeably, sorafenib efficiently induced apoptosis, even in HBx-expressing HepG2 cells, indicating that the HBx protein does not attenuate sorafenib-induced apoptosis. We next investigated if sorafenib modulates autophagy, allowing HCC cells to overcome the chemoresistance conferred by the HBx protein. Although autophagy plays a cytoprotective role against sorafenib-induced lethality, sorafenib was effective irrespective of HBx protein overexpression. We next examined if sorafenib exerts its cytotoxic effect via direct effects on the HBx protein. Importantly, sorafenib decreased HBx protein stability through a proteasome-dependent degradation pathway. Moreover, sorafenib decreased HBV gene expression and viral promoter activity. Taken together, sorafenib efficiently induces apoptotic cell death in HBx-expressing HCC cells via the downregulation of the HBx protein, a key factor in the anti-cancer drug resistance observed in HBV-induced HCC.
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
authors.forename: Hye Uk
authors.initials: HU
authors.lastname: Jung
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
authors.forename: Ki Soo
authors.initials: KS
authors.lastname: Yoo
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, South Korea.
authors.forename: JaeHun
authors.initials: J
authors.lastname: Cheong
authors.affiliation: Department of Oral Anatomy and Cell Biology, School of Dentistry, Yangsan Campus of Pusan National University, Yangsan 626-870, South Korea.
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Park
authors.affiliation: Departments of Dental Pharmacology and Biophysics, School of Dentistry and Research Institute for Oral Biotechnology, Yangsan Campus of Pusan National University, Yangsan 626-870, South Korea.
authors.forename: Il
authors.initials: I
authors.lastname: Yun
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea. Electronic address: yhyoo@dau.ac.kr.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D055550:Protein Stability; D000077157:Sorafenib; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D009536:Niacinamide; D005047:Etoposide; D000077157:Sorafenib; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin
keywords: Apoptosis; HBx protein; HCC; Hepatitis B virus; Sorafenib