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

Research output: Contribution to journalReview article

Abstract

We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through activation of c-Jun-NH2-kinase. We also found that some human cancers are resistant to Ad-REK-induced apoptosis. In this review, we focus on the resistance to Ad-REIC and the re-sensitization of the resistance. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. The infection efficiency of the adenovirus vector and the expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By comparing the expression level of proteins between the resistant clones and parental PC3 cells, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. The expression levels of BiP and the 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 vitro. 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 is also useful as a target molecule to overcome resistance to gene-therapeutic Ad-REIC.

Original languageEnglish
Pages (from-to)531-537
Number of pages7
JournalNishinihon Journal of Urology
Volume74
Issue number10
Publication statusPublished - Oct 2012

Fingerprint

Prostatic Neoplasms
Down-Regulation
Clone Cells
Apoptosis
Genes
Adenoviridae Infections
Neoplasms
Therapeutic Uses
Therapeutics
Tumor Suppressor Genes
Adenoviridae
Small Interfering RNA
Proteins
Phosphotransferases
Cell Line

Keywords

  • BiP
  • Dkk-3
  • Gene therapy
  • GRP78
  • REIC

ASJC Scopus subject areas

  • Urology

Cite this

@article{f004d46012d14fc8ba06ef01e19592db,
title = "Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3",
abstract = "We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through activation of c-Jun-NH2-kinase. We also found that some human cancers are resistant to Ad-REK-induced apoptosis. In this review, we focus on the resistance to Ad-REIC and the re-sensitization of the resistance. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. The infection efficiency of the adenovirus vector and the expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By comparing the expression level of proteins between the resistant clones and parental PC3 cells, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. The expression levels of BiP and the 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 vitro. 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 is also useful as a target molecule to overcome resistance to gene-therapeutic Ad-REIC.",
keywords = "BiP, Dkk-3, Gene therapy, GRP78, REIC",
author = "Ryuta Tanimoto",
year = "2012",
month = "10",
language = "English",
volume = "74",
pages = "531--537",
journal = "Nishinihon Journal of Urology",
issn = "0029-0726",
publisher = "Kyushu University, Faculty of Science",
number = "10",

}

TY - JOUR

T1 - Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3

AU - Tanimoto, Ryuta

PY - 2012/10

Y1 - 2012/10

N2 - We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through activation of c-Jun-NH2-kinase. We also found that some human cancers are resistant to Ad-REK-induced apoptosis. In this review, we focus on the resistance to Ad-REIC and the re-sensitization of the resistance. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. The infection efficiency of the adenovirus vector and the expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By comparing the expression level of proteins between the resistant clones and parental PC3 cells, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. The expression levels of BiP and the 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 vitro. 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 is also useful as a target molecule to overcome resistance to gene-therapeutic Ad-REIC.

AB - We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through activation of c-Jun-NH2-kinase. We also found that some human cancers are resistant to Ad-REK-induced apoptosis. In this review, we focus on the resistance to Ad-REIC and the re-sensitization of the resistance. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. The infection efficiency of the adenovirus vector and the expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By comparing the expression level of proteins between the resistant clones and parental PC3 cells, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. The expression levels of BiP and the 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 vitro. 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 is also useful as a target molecule to overcome resistance to gene-therapeutic Ad-REIC.

KW - BiP

KW - Dkk-3

KW - Gene therapy

KW - GRP78

KW - REIC

UR - http://www.scopus.com/inward/record.url?scp=84868151165&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868151165&partnerID=8YFLogxK

M3 - Review article

VL - 74

SP - 531

EP - 537

JO - Nishinihon Journal of Urology

JF - Nishinihon Journal of Urology

SN - 0029-0726

IS - 10

ER -