title: Leptomycin B enhances CDDP-sensitivity via nuclear accumulation of p53 protein in HPV-positive cells.
abstract: Cervical cancer, which commonly contains a wild-type p53 gene, is highly correlated with human papilloma virus (HPV) infection. Because the oncoprotein E6, derived from HPV, inhibits the function of p53 protein, the inhibition of apoptosis via the p53 pathway by HPV may be related to cisplatin (CDDP)-sensitivity in cervical cancer. We conducted the present study to determine whether and how HPV is related to CDDP-sensitivity in HPV-positive cervical cancer cells. We used cervical carcinoma cell lines HeLa with integrated HPV 18 and SiHa with integrated HPV 16. An HPV-negative cell line, Yumoto, with wild-type p53 gene was used as a control. Leptomycin B (LMB) enhanced sensitivity to CDDP and CDDP-induced apoptosis in HeLa and SiHa cells, but not in Yumoto cells. After exposure to LMB or CDDP alone, we observed weak p53 staining in HeLa, SiHa and Yumoto cells. Nuclear p53 staining was significantly increased by combined treatment with CDDP and LMB in HeLa and SiHa cells, but not in Yumoto cells. The expression of p53 and Bax protein increased with exposure to CDDP and was enhanced by LMB in HeLa and SiHa cells. The present study demonstrated that LMB enhanced CDDP-sensitivity via nuclear accumulation of p53 protein in HPV-positive cells.
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, 36-1 Nishimachi, Yonago 683-8504.
authors.forename: Jun
authors.initials: J
authors.lastname: Naniwa
authors.forename: Junzo
authors.initials: J
authors.lastname: Kigawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Akeshima
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Kanamori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oishi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iba
authors.forename: Naoki
authors.initials: N
authors.lastname: Terakawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004357:Drug Synergism; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D030361:Papillomavirus Infections; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014412:Tumor Virus Infections; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000821:virology; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D002945:Cisplatin; C038753:leptomycin B