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REIC/Dkk-3 is a tumor suppressor gene that was first identified as a genedownregulated in association with immortalization of normal human fibroblasts.We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed atumor-specific killing effect on a wide range of cancers. However, some humancancers, bladder cancers in particular, are resistant to Ad-REIC. In this study,we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1)and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among sixcell lines examined were resistant to Ad-REIC. Among the cell lines, the resistanceof two cell lines was probably due to low infection efficiency of the adenovirus.PINK1-specific siRNA remarkably downregulated Bcl-xL and TRAP1 proteins and upregulatedBAX protein expression. Finally, downregulation of PINK1 partially sensitizedthe other three cell lines that were resistant to Ad-REIC. This sensitizationwas associated with increasing production of reactive oxygen species (ROS). Theseresults indicate that PINK1 is one of the key molecules for the mitochondrialprotection system and that PINK1 can be a new target molecule to sensitize bladdercancer cells that are resistant to Ad-REIC.

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1