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

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.