Creation of a LIGHT mutant with the capacity to evade the decoy receptor for cancer therapy

Morishige, Tomohiro; Yoshioka, Yasuo; Inakura, Hiroshi; Tanabe, Aya; Yao, Xinglei; Tsunoda, Shin-ichi; Tsutsumi, Yasuo; Mukai, Yohei; Okada, Naoki; Nakagawa, Shinsaku

doi:10.1016/j.biomaterials.2010.01.022

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…The mutation of LIGHT residues E115-L120 significantly reduced the affinity for DcR3, suggesting an important role of this loop in recognition (Morishige et al, 2010). …”

Section: Resultsmentioning

confidence: 99%

Mechanistic Basis for Functional Promiscuity in the TNF and TNF Receptor Superfamilies: Structure of the LIGHT:DcR3 Assembly

Liu¹,

Zhan²,

Cheng³

et al. 2014

Structure

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Summary LIGHT initiates intracellular signaling via engagement of the two TNF receptors, HVEM and LTβR. In humans, LIGHT is neutralized by DcR3, a unique soluble member of the TNFR superfamily, which tightly binds LIGHT and inhibits its interactions with HVEM and LTβR. DcR3 also neutralizes two other TNF ligands, FasL and TL1A. Due to its ability to neutralize three distinct different ligands, DcR3 contributes to a wide range of biological and pathological processes, including cancer and autoimmune diseases. However, the mechanisms which support the broad specificity of DcR3 remain to be fully defined. We report the structures of LIGHT and the LIGHT:DcR3 complex, which reveal the structural basis for the DcR3-mediated neutralization of LIGHT and afford new insights into DcR3 function and binding promiscuity. Based on these structures, we designed novel LIGHT mutants with altered affinities for DcR3 and HVEM, which may represent new mechanistically informative probe reagents.

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“…The mutation of LIGHT residues E115-L120 significantly reduced the affinity for DcR3, suggesting an important role of this loop in recognition (Morishige et al, 2010). …”

Section: Resultsmentioning

confidence: 99%

Mechanistic Basis for Functional Promiscuity in the TNF and TNF Receptor Superfamilies: Structure of the LIGHT:DcR3 Assembly

Liu¹,

Zhan²,

Cheng³

et al. 2014

Structure

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“…It has been reported that DcR3 has three ligands: FasL, TNF-like molecule 1A (TL1A) and LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for binding to herpes virus entry mediator, a receptor expressed by T lymphocytes). DcR3 apparently could not only block apoptosis of Fas, TL1A and LIGHT by inhibiting the FasL–Fas, TL1A–death receptor 3 (DR3) and LIGHT–lymphotoxin β receptor interactions [22-24] but also suppress immune surveillance by blocking T-cell costimulation mediated by TL1A and LIGHT [25,26]. Our previous study indicated that silencing DcR3 by lentivirus-mediated DcR3 RNAi enhances the effect of FasL and inhibits tumor growth in vitro and in vivo [27].…”

Section: Discussionmentioning

confidence: 99%

Decoy receptor 3 (DcR3) overexpression predicts the prognosis and pN2 in pancreatic head carcinoma

Zhou

Song

et al. 2014

World J Surg Onc

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BackgroundThis study was carried out to examine decoy receptor 3 (DcR3) expression and investigate its clinical and prognostic significance in patients with pancreatic head carcinoma.MethodsTissue samples were obtained from 50 patients with pancreatic head carcinoma. DcR3 protein expression in tissues and sera was assessed by immunohistochemistry and ELISA. Correlations between DcR3 and clinicopathologic features and prognoses were analyzed statistically.ResultsSerum DcR3 levels were significantly elevated in patients with pancreatic head carcinoma compared with patients with cystadenoma and healthy individuals (P < 0.01 and P < 0.01, respectively). DcR3 overexpression correlated with lymph node metastases and TNM stages (P < 0.05 and P < 0.05, respectively). Median overall survival for the high DcR3 group was 16.3 months, compared to 21.6 months for the low DcR3 group (P < 0.05). In the low DcR3 group, no significant difference was found in the overall survival between patients who underwent standard pancreatoduodenectomy (SPD) and those who had radical pancreatoduodenectomy (RPD) (P > 0.05). In the high DcR3 group, the median overall survival rates were 16.8 months in the RPD group and 13.5 months in the SPD group (P < 0.05).ConclusionsWe found that DcR3 was overexpressed in pancreatic head carcinoma. The patients with high DcR3 levels had higher pN2 stages than those with low DcR3 levels. Detecting serum DcR3 level preoperatively might be an additional approach for evaluating pN2 stage and guiding the range of lymphadenectomy.

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“…DcR3 can block the effects of FasL, TL1A and LIGHT by inhibiting the FasL-Fas, TL1A-death receptor 3 (DR3) and LIGHT-HVEM interaction (22)(23)(24). Evidence has shown that DcR3 not only protects tumor cells from apoptosis induced by FasL, LIGHT and TL1A, but also suppresses immune surveillance by blocking T cell costimulation mediated by TL1A and LIGHT (25,26).…”

Section: Discussionmentioning

confidence: 99%

Silencing of decoy receptor 3 (DcR3) expression by siRNA in pancreatic carcinoma cells induces Fas ligand-mediated apoptosis in vitro and in vivo

Zhou

Song

et al. 2013

International Journal of Molecular Medicine

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Abstract. Decoy receptor 3 (DcR3) is abundantly expressed in human tumors and protects cells from a wide range of apoptotic stimuli. In this study, we demonstrate that DcR3 is overexpressed in pancreatic carcinoma cells, and that the pancreatic carcinoma cell lines, Panc-1 and SW1990, are resistant to Fas ligand (FasL)-mediated apoptosis. To further define the function of DcR3 in cell growth and apoptosis, we used small interfering RNA (siRNA) to knockdown the expression of the DcR3 gene in Panc-1 and SW1990 cells. Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro. In addition, the downregulation of DcR3 modulated the cell apoptotic regulators, Fas-associated death domain (FADD), caspase-3 and caspase-8, thus triggering cell apoptosis. Furthermore, the knockdown of DcR3 inhibited the growth of Panc-1 tumor xenografts. Taken together, our findings indicate that DcR3 is important in cancer progression and may be a used as a potential therapeutic target for the gene therapy of pancreatic carcinoma.

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Creation of a LIGHT mutant with the capacity to evade the decoy receptor for cancer therapy

Cited by 17 publications

References 36 publications

Mechanistic Basis for Functional Promiscuity in the TNF and TNF Receptor Superfamilies: Structure of the LIGHT:DcR3 Assembly

Mechanistic Basis for Functional Promiscuity in the TNF and TNF Receptor Superfamilies: Structure of the LIGHT:DcR3 Assembly

Decoy receptor 3 (DcR3) overexpression predicts the prognosis and pN2 in pancreatic head carcinoma

Silencing of decoy receptor 3 (DcR3) expression by siRNA in pancreatic carcinoma cells induces Fas ligand-mediated apoptosis in vitro and in vivo

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