title: Exogenous p53 and ASPP2 expression enhances rAdV-TK/ GCV-induced death in hepatocellular carcinoma cells lacking functional p53.
abstract: Suicide gene therapy using herpes simplex virus-1 thymidine kinase (HSV-TK) in combination with ganciclovir (GCV) has emerged as a potential new method for treating cancer. We hypothesize that the efficacy of HSV-TK/GCV therapy is at least partially dependent on p53 status in hepatocellular carcinoma (HCC) patients. Using recombinant adenoviral vectors (rAdV), TK, p53, and ASPP2 were overexpressed individually and in combination in Hep3B (p53 null) and HepG2 (p53 wild-type) cell lines and in primary HCC tumor cells. p53 overexpression induced death in Hep3B cells, but not HepG2 cells. ASPP2 overexpression increased rAdV-TK/GCV-induced HepG2 cell death by interacting with endogenous p53. Similarly, ASPP2 reduced survival in rAdV-TK/GCV-treated primary HCC cells expressing p53 wild-type but not a p53 R249S mutant. Mutated p53 was unable to bind to ASPP2, suggesting that the increase in rAdV-TK/GCV-induced cell death resulting from ASPP2 overexpression was dependent on its interaction with p53. Additionally, γ-H2AX foci, ATM phosphorylation, Bax, and p21 expression increased in rAdV-TK/GCV-treated HepG2 cells as compared to Hep3B cells. This suggests that the combined use of HSV-TK, GCV, rAdV-p53 and rAdV-ASPP2 may improve therapeutic efficacy in HCC patients lacking functional p53.
authors.affiliation: Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.|Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.|Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Guo
authors.affiliation: Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Feili
authors.initials: F
authors.lastname: Wei
authors.affiliation: Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Yin
authors.affiliation: Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.|Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000494:pharmacology*; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C495901:TP53 protein, human; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: ASPP2; ganciclovir; gene therapy; hepatocellular carcinoma; p53