Retrovirus-mediated transduction of a short hairpin RNA gene for GRP78 fails to downregulate GRP78 expression but leads to cisplatin sensitization in HeLa cells.

Glucose-regulated protein 78 (GRP78) is expressed abundantly in various types of cancer cells and is believed to contribute to chemotherapeutic resistance. In this study, we investigated the effect of a continuous approach for the expression of a short hairpin RNA (shRNA) targeted to GRP78 with retrovirus transduction on the sensitivity to the anticancer drugs VP-16 and cisplatin. The reduction of GRP78 expression failed, and the expression of GRP94 and P5 chaperon mRNA increased; this increase was associated with a mild activation of the unfolded protein response in HeLa cells, which were stably transduced with GRP78 shRNA gene. The transduced cells exhibited similar sensitivity to VP-16-induced cell death when compared to control GFP shRNA gene-transduced cells. However, sensitivity to cisplatin-induced cell death was higher in GRP78 shRNA gene-transduced cells compared to control cells. These results demonstrate that the continuous or prolonged approach targeting GRP78 confers sensitization of HeLa cells to cisplatin independently of the down-regulation of GRP78 expression. The role of the unfolded protein response in sensitization to cisplatin is discussed.