Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3
✍ Scribed by Ryuta Tanimoto; Masakiyo Sakaguchi; Fernando Abarzua; Ken Kataoka; Kaoru Kurose; Hitoshi Murata; Yasutomo Nasu; Hiromi Kumon; Nam-Ho Huh
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- French
- Weight
- 383 KB
- Volume
- 126
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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.