Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3

Ryuta Tanimoto, Masakiyo Sakaguchi, Fernando Abarzua, Ken Kataoka, Kaoru Kurose, Hitoshi Murata, Yasutomo Nasu, Hiromi Kumon, Nam Ho Huh

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

We have recently shown that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) exhibits a potent tumor-specific cell-killing function for various human cancers. It has also become evident that some human cancers are resistant to Ad-REIC-induced apoptosis. The aim of the present study was to determine the molecular mechanisms of resistance to Ad-REIC. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. Infection efficiency of the adenovirus vector and expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By screening for alteration in levels and functional status of proteins involved in Ad-REIC-induced apoptosis, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. Expression levels of BiP and rates of apoptosis induced by Ad-REIC were inversely correlated. Down-regulation of BiP with siRNA sensitized the resistant cells to Ad-REIC in vivo as well as in culture. These results indicate that BiP is a major determinant of resistance to Ad-REIC-induced apoptosis. Thus BiP is useful for diagnosis of inherent and acquired resistance of cancers and also as a target molecule to overcome resistance to the gene therapeutic Ad-REIC.

Original languageEnglish
Pages (from-to)1562-1569
Number of pages8
JournalInternational Journal of Cancer
Volume126
Issue number7
DOIs
Publication statusPublished - Apr 1 2010

Keywords

  • Apoptosis
  • Dkk
  • ER stress
  • GRP78
  • REIC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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