Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells
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Michihiro Yabe1, Kei Ishibashi1, Akifumi Onagi1, Ryo Tanji1, Ruriko Honda-Takinami1, Tomoyuki Koguchi1, Kanako Matsuoka1, Seiji Hoshi1, Junya Hata1, Masao Kataoka1, Soichiro Ogawa1, Hiroyuki Hiraki1, Nobuhiro Haga1 and Yoshiyuki Kojima1
1Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
Kei Ishibashi, email: [email protected]
Keywords: renal cell carcinoma; TRAIL-R1/DR4; IFN; SOCS3; tocilizumab
Received: May 29, 2018 Accepted: July 13, 2018 Published: August 03, 2018
Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer that is expressed in natural killer cells, whose cytotoxicity is activated by interferon (IFN). We investigated the effect of suppressor of cytokine signaling (SOCS) 3 on the expression of TRAIL receptors (DR4) and on TRAIL sensitivity in renal cell carcinoma (RCC) cells.
Methods: Vector expression, RNA interference and IL-6 receptor antibody tocilizumab were used to investigate the functional role of SOCS3 in DR4 expression. Immunoprecipitation was employed to detect the biochemical interaction between SOCS3 and DR4. The expression of DR4 induced by combination with IFN-α and tocilizumab was also examined by immunohistochemical staining using mice xenograft model.
Results: DR4 expression was up-regulated by IFN stimulation in RCC cells. 786-O cells were resistant to TRAIL and showed higher SOCS3 expression. ACHN cells showed higher DR4 expression and lower SOCS3 expression. Suppression of SOCS3 up-regulated DR4 expression and enhanced the TRAIL sensitivity in 786-O cells. In ACHN cells, DR4 expression was down-regulated by transfection with pCI-SOCS3, and the cells became resistant to TRAIL. Immunoprecipitation revealed the biochemical interaction between SOCS3 and DR4. A marked increase in IFN-induced DR4 protein expression after tocilizumab treatment was observed by immunohistochemical staining in the tumor from the mice xenograft model.
Conclusions: Our results indicate that IFN and SOCS3 regulate DR4 expression in RCC cells. Combination therapy with IFN-α, tocilizumab and an anti-DR4 agonistic ligand appears to effectively inhibit advanced RCC cell growth.
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