Sorafenib with doxorubicin augments cytotoxicity to renal cell cancer through PERK inhibition

Abstract

Abstract. Although cytokine therapy involving interleukin-2 or interferon-· has been employed for metastatic renal cell cancer (RCC) treatment, these therapies yielded limited response and benefit. Recently, several molecular-targeted agents have become available, and one newly developed anti-RCC agent, sorafenib , is known to target multiple kinases. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2· (eIF2·) and induce cell cycle arrest at G2/M phase and increase cell death. One of eIF2· kinases, PERK was responsible for eIF2· phosphorylation in RCC cells and PERK knockdown induced cell death similar to sorafenib treatment. The efficiency of sorafenib treatment correlated with phosphorylation level of eIF2· and nuclear Nrf2 expression level in eight RCC cell lines. Furthermore, sorafenib made Caki-1 and 786-O cells, but not ACHN cells sensitive to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized Caki-1 and 786-O cells, but not ACHN cells to oxidative stress. In conclusion, levels of phospho-eIF2· and nuclear Nrf2 expression level in RCC might be a predictor of outcome in sorafenib treatment. In addition, PERK inhibition as well as sorafenib plus doxorubicin might be a promising therapeutic approach for RCC characterized by high levels of phosphorylatedeIF2· and nuclear Nrf2.