In vivo evaluation of the role of DNp73α protein in regulating the p53-dependent apoptotic pathway after treatment with cytotoxic drugs

Maria Antonietta Sabatino, Sara Previdi, Massimo Broggini

Research output: Contribution to journalArticle

Abstract

The amino terminus truncated p73 isoform, ΔNp73α, shows dominant negative behavior toward TAp73 and wild-type p53, and has oncogenic potential. By contrast, we recently showed that in HCT116 clones forced expression of ΔNp73α did not increase in vitro cellular resistance to anticancer agents. The purpose of this study was to characterize in vivo models and to investigate the functional interaction between the ΔNp73α isoform and the p53 pathway. Human colon carcinoma HCT116 clones expressing inducible ΔNp73α (HCT116/DN3, HCT116/DN14) and HCT116/8a (transfected with the mock empty vector), transplanted in immunodeficient nude mice, were used to study the antitumor activity of cis-diammine-dichloro-platinum (cDDP) (4 mg/kg, i.v., q7d × 3) and Doxorubicin (DX) (7.5 mg/kg. i.v., q7d × 3), with or without tetracycline-induced ΔNp73α overexpression. ΔNp73α expression was confirmed by RT-PCR, immunoblotting and immunohistochemical analysis. ΔNp73α subcellular localization after DX treatment was checked by an immunofluorescence assay. Western blot was used to analyze p53, p21, Bax, Bcl-2 and p53AIP1 expression. ΔNp73α overexpression did not modify the antitumor activity of either DX or cDDP in xenograft models. DX reduced ΔNp73α protein expression, without affecting its nuclear localization. p53, p21, Bax and p53AIP1 protein expression increased and Bcl-2 decreased in HCT116 clone derived tumors 24 hr after DX exposure, independently of the presence of ΔNp73α. Overexpression of ΔNp73α does not affect tumor growth in vitro, does not increase the resistance of established tumors to anticancer agents and does not antagonize p53 apoptotic functions.

Original languageEnglish
Pages (from-to)506-513
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number3
DOIs
Publication statusPublished - Feb 1 2007

Keywords

  • Apoptosis
  • Colon carcinoma
  • DNp73α
  • In vivo
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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