Cell death‐independent activities of the death receptors <scp>CD</scp>95, <scp>TRAILR</scp>1, and <scp>TRAILR</scp>2

Siegmund, Daniela; Lang, Isabell; Wajant, Harald

doi:10.1111/febs.13968

Cited by 63 publications

(51 citation statements)

References 195 publications

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“…29 TRAIL binds to cell surface death receptor 4 (DR4; TRAIL-R1) or death receptor 5 (DR5; TRAIL-R2), which further recruit the adaptor Fas-associated protein with death domain (FADD) and caspase 8, leading to the activation of caspase 3. 30,31 In the current study, our findings demonstrated that ixazomib sensitizes TRAIL-induced apoptosis via CHOPdependent DR5 induction. Our results highlight the newest biological functions of ixazomib in the regulation of apoptosis and the need to further investigate the potential treatment of CRC using a combination with ixazomib and TRAIL.…”

Section: Introductionsupporting

confidence: 62%

Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

Yue

Sun

2018

Cancer Biology & Therapy

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Background: Ixazomib (Ninlaro), a novel proteasome inhibitor, has been developed for the treatment of many cancers and has demonstrated anti-tumor efficacy against various malignancies. However, the mechanism of the anti-tumor effect of ixazomib in colorectal cancer (CRC) cells remains unclear. Methods: MTS and flow cytometry were performed to determine the effect of ixazomib on CRC cells. Western blotting and real-time RT-PCR were performed to detect ixazomib-induced DR5 upregulation. ChIP was performed to detect CHOP binding to DR5 promoter. Finally, xenograft experiments were carried out to measure the antitumor effect of ixazomib in vivo. Results: In this study, we revealed the mechanism by which ixazomib inhibits the growth of CRC cells. Our findings indicated that ixazomib treatment induces CHOP-dependent DR5 induction, irrespective of p53 status. Furthermore, DR5 is necessary for ixazomib-mediated apoptosis. Ixazomib also synergized with TRAIL to induce marked apoptosis via DR5 in CRC cells. Conclusions: Our findings further suggested that ixazomib sensitizes TRAIL/death receptor signaling pathway-targeted CRC and suggested that DR5 induction could be a valuable indicator of ixazomib sensitivity.

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Section: Introductionsupporting

confidence: 62%

Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

Yue

Sun

2018

Cancer Biology & Therapy

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“…Transmembrane CD95L (m-CD95L) is a potent inducer of cell death ( 33 ). m-CD95L can be cleaved by different metalloproteases and although s-CD95L interacts with CD95 it fails to trigger cell death ( 34 , 35 ).…”

Section: Drs Belonging To the Tumor Necrosis Factor (Tnf) Receptor (Tmentioning

confidence: 99%

CD95/Fas, Non-Apoptotic Signaling Pathways, and Kinases

et al. 2017

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Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate. The receptor CD95 (also named Fas or apoptosis antigen 1) belongs to the tumor necrosis factor (TNF) receptor superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Because mutations of this receptor or its ligand lead to autoimmune disorders such as systemic lupus erythematosus (SLE) and cancers, CD95 and CD95L were initially thought to play a role in immune homeostasis and tumor elimination via apoptotic signaling pathways. However, recent data reveal that CD95 also evokes non-apoptotic signals, promotes inflammation, and contributes to carcinogenesis; therefore, it is difficult to dissect its apoptotic effects from its non-apoptotic effects during pathogenesis of disease. CD95L is cleaved by metalloproteases and so exists in two different forms: a transmembrane form and a soluble ligand (s-CD95L). We recently observed that the soluble ligand is overexpressed in serum from patients with triple-negative breast cancer or SLE, in whom it contributes to disease severity by activating non-apoptotic signaling pathways and promoting either metastatic dissemination or accumulation of certain T cell subsets in damaged organs. Here, we discuss the roles of CD95 in modulating immune functions via induction of mainly non-apoptotic signaling pathways.

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“…Activation of cell surface receptors (death receptors) triggers the extrinsic apoptotic pathway. The death receptors (DR) such as fibroblast-associated antigen (Fas), TNF-related apoptosis-inducing ligand (TRAIL), tumor necrosis factor receptor-1 (TNFR1), DR3, DR4, DR5, and DR6 transmit signals from extracellular ligand binding domains to cytoplasmic death domains [ 50 , 51 ]. Upon ligand binding, a death inducing signaling complex (DISC) is formed by the interaction of DRs with the Fas-associated death domain (FADD) and procaspase-8.…”

Section: Targeting Cancer Cells By Apoptosis Pathwaysmentioning

confidence: 99%

“…Upon ligand binding, a death inducing signaling complex (DISC) is formed by the interaction of DRs with the Fas-associated death domain (FADD) and procaspase-8. Within DISC, procaspase-8 is activated by auto-proteolysis and becomes free which, in turn, either activates the type 1 extrinsic apoptotic pathway by activating downstream effector caspase-3 or the type 2 extrinsic apoptotic pathway by the truncation of Bid, a pro-apoptotic member of the Bcl-2 protein family [ 51 , 52 , 53 ].…”

Section: Targeting Cancer Cells By Apoptosis Pathwaysmentioning

confidence: 99%

Deoxyelephantopin and Isodeoxyelephantopin as Potential Anticancer Agents with Effects on Multiple Signaling Pathways

et al. 2017

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Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and isodeoxyelephantopin (IDET) are sesquiterpene lactone components of “Elephantopus scaber and Elephantopus carolinianus”, traditional Chinese medicinal herbs that have long been used as folk medicines to treat liver diseases, diabetes, diuresis, bronchitis, fever, diarrhea, dysentery, cancer, and inflammation. Recently, the anticancer activity of DET and IDET has been widely investigated. Here, our aim is to review the current status of DET and IDET, and discuss their anticancer activity with specific emphasis on molecular targets and mechanisms used by these compounds to trigger apoptosis pathways which may help to further design and conduct research to develop them as lead therapeutic drugs for cancer treatments. The literature has shown that DET and IDET induce apoptosis through multiple signaling pathways which are deregulated in cancer cells and suggested that by targeting multiple pathways simultaneously, these compounds could selectively kill cancer cells. This review suggests that DET and IDET hold promising anticancer activity but additional studies and clinical trials are needed to validate and understand their therapeutic effect to develop them into potent therapeutics for the treatment of cancer.

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Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

Cited by 63 publications

References 195 publications

Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

CD95/Fas, Non-Apoptotic Signaling Pathways, and Kinases

Deoxyelephantopin and Isodeoxyelephantopin as Potential Anticancer Agents with Effects on Multiple Signaling Pathways

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