Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

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Abstract

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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Most cited references 32

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Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease.

Norihiro Nishimoto, Yuzuru Kanakura, Katsuyuki Aozasa … (2005)

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.

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Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial.

Norihiro Nishimoto, Kazuyuki Yoshizaki, Nobuyuki Miyasaka … (2004)

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

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Natural Killer (NK) Cell–mediated Cytotoxicity: Differential Use of TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells

Loris Zamai, Manzoor Ahmad, Ian M. Bennett … (1998)

Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or secreted cytokines (tumor necrosis factor [TNF]-α) to induce target cell death. Fas belongs to the TNF receptor family of molecules, containing a conserved intracytoplasmic “death domain” that indirectly activates the caspase enzymatic cascade and ultimately apoptotic mechanisms in numerous cell types. Two additional members of this family, DR4 and DR5, transduce apoptotic signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL) that, like FasL, belongs to the growing TNF family of molecules. Here, we report that TRAIL produced or expressed by different populations of primary human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During differentiation NK cells, sequentially and differentially, use distinct members of the TNF family or granule exocytosis to mediate target cell death. Phenotypically immature CD161+/CD56− NK cells mediate TRAIL-dependent but not FasL- or granule release–dependent cytotoxicity, whereas mature CD56+ NK cells mediate the latter two.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 3 August 2018

Publication date (Electronic): 3 August 2018

Volume: 9

Issue: 60

Pages: 31697-31708

Affiliations

¹ Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan

Author notes

Correspondence to: Kei Ishibashi, keikun@ 123456fmu.ac.jp

Article

Publisher ID: 25851

DOI: 10.18632/oncotarget.25851

PMC ID: 6114968

PubMed ID: 30167088

SO-VID: 6467d1c8-9417-489d-b278-b5506df71148

License:

This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

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Abstract

Background

Methods

Results

Conclusions

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Gamma Delta T cells

Most cited references 32

Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease.

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial.

Natural Killer (NK) Cell–mediated Cytotoxicity: Differential Use of TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells

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