title: Trichostatin A sensitizes HBx-expressing liver cancer cells to etoposide treatment.
abstract: Agents commonly used in cancer chemotherapy rely on the induction of cell death via apoptosis, mitotic catastrophe, premature senescence and autophagy. Chemoresistance is the major factor limiting long-term treatment success in patients with hepatocellular carcinoma (HCC). Recent studies have revealed that the hepatitis B virus X protein (HBx) exerts anti-apoptotic effects, resulting in an increased drug resistance in HCC cells. In this study, we showed that etoposide treatment activated caspase-8 and caspase-3, leading to cleavages of p53, Bid and PARP, which subsequently induced apoptosis. Furthermore, p53 and Bid were accumulated in cytoplasm following etoposide treatment. However, HBx significantly attenuated etoposide-induced cell death. In HBx-expressing cells, despite the translocation of p53 and Bid to cytoplasm, the activation of caspases was inhibited. Furthermore, the phosphorylation of extracellular-signal-regulated kinase (ERK) was markedly increased in HBx-expressing cells. Moreover, the pretreatment with trichostatin A (TSA, a histone deacetylase inhibitor) or TSA in combination with etoposide significantly sensitized HCC cells to apoptosis by inhibiting ERK phosphorylation, reactivating caspases and PARP, and inducing translocation of p53 and Bid to cytoplasm. Collectively, HBx reduces the sensitivity of HCC cells to chemotherapy. TSA in combination with etoposide can significantly overcome the increased resistance of HBx-expressing HCC cells to chemotherapy.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
authors.forename: Chris Z Y
authors.initials: CZ
authors.lastname: Zhang
authors.forename: H T
authors.initials: HT
authors.lastname: Zhang
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D006877:Hydroxamic Acids; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases