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

Masaki Shiota, Masatoshi Eto, Akira Yokomizo, Yasuhiro Tada, Ario Takeuchi, Daisuke Masubuchi, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Takeshi Uchiumi, Narihito Seki, Seiji Naito

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Although cytokine therapy involving interleukin-2 or interferon-α 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 (BAY 43-9006), is known to target multiple kinases. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2α (eIF2α) and induce cell cycle arrest at G2/M phase and increase cell death. One of eIF2α kinases, PERK was responsible for eIF2α phosphorylation in RCC cells and PERK knockdown induced cell death similar to sorafenib treatment. The efficiency of sorafenib treatment correlated with phosphorylation level of eIF2α 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-eIF2α 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 phosphorylatedeI-F2α and nuclear Nrf2.

Original languageEnglish
Pages (from-to)1521-1531
Number of pages11
JournalInternational journal of oncology
Volume36
Issue number6
DOIs
Publication statusPublished - Jun 1 2010

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Renal Cell Carcinoma
Doxorubicin
Eukaryotic Initiation Factor-2
Phosphorylation
Oxidative Stress
Cell Death
sorafenib
G2 Phase
Cell Cycle Checkpoints
Cell Division
Interferons
Hydrogen Peroxide
Interleukin-2
Phosphotransferases
Therapeutics
Cytokines
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Sorafenib with doxorubicin augments cytotoxicity to renal cell cancer through PERK inhibition. / Shiota, Masaki; Eto, Masatoshi; Yokomizo, Akira; Tada, Yasuhiro; Takeuchi, Ario; Masubuchi, Daisuke; Inokuchi, Junichi; Tatsugami, Katsunori; Kuroiwa, Kentaro; Uchiumi, Takeshi; Seki, Narihito; Naito, Seiji.

In: International journal of oncology, Vol. 36, No. 6, 01.06.2010, p. 1521-1531.

Research output: Contribution to journalArticle

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