Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer.

ABSTRACT: Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.

SUBMITTER: Moon JH

PROVIDER: S-EPMC4694961 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: roles of XIAP and cIAPs.

Project description:TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it shows apoptosis-inducing activity in transformed, but not in normal, cells. As with most anticancer agents, however, its clinical use is restricted by either inherent or acquired resistance by cancer cells. We demonstrate here that small-molecule SMAC mimetics that antagonize the inhibitor of apoptosis proteins (IAP) potently sensitize previously resistant human cancer cell lines, but not normal cells, to TRAIL-induced apoptosis, and that they do so in a caspase-8-dependent manner. We further show that the compounds have no cytotoxicity as single agents. Also, we demonstrate that several IAP family members likely participate in the modulation of cellular sensitivity to TRAIL. Finally, we note that the compounds that sensitize cancer cells to TRAIL are the most efficacious in binding to X-linked IAP, and in inducing cellular-IAP (cIAP)-1 and cIAP-2 degradation. Our studies thus describe valuable compounds that allow elucidation of the signaling events occurring in TRAIL resistance, and demonstrate that these agents act as potent TRAIL-sensitizing agents in a variety of cancer cell lines.

| S-EPMC3947130 | biostudies-literature

XIAP and cIAP1 amplifications induce Beclin 1-dependent autophagy through NFκB activation.

Project description:Perturbations in autophagy and apoptosis are associated with cancer development. XIAP and cIAP1 are two members of the inhibitors of apoptosis protein family whose expression is elevated in different cancers. Here we report that XIAP and cIAP1 induce autophagy by upregulating the transcription of Beclin 1, an essential autophagy gene. The E3 ubiquitin ligase activity of both proteins activates NFκB signalling, leading to the direct binding of p65 to the promoter of Beclin 1 and to its transcriptional activation. This mechanism may be relevant in cancer cells, since we found increased levels of autophagy in different B-cell lymphoma-derived cell lines where XIAP is overexpressed and pharmacological inhibition of XIAP in these cell lines reduced autophagosome biogenesis. Thus, the chemotherapy resistance associated with XIAP and cIAP1 overexpression observed in several human cancers may be, at least in part, due to the Beclin 1-dependent autophagy activation by IAPs described in this study. In this context, the disruption of this increased autophagy might represent a valuable pharmacological tool to be included in combined anti-neoplastic therapies.

| S-EPMC4406300 | biostudies-literature

Potent and selective small-molecule inhibitors of cIAP1/2 proteins reveal that the binding of Smac mimetics to XIAP BIR3 is not required for their effective induction of cell death in tumor cells.

Project description:Cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked inhibitor of apoptosis protein (XIAP) are key apoptosis regulators and promising new cancer therapeutic targets. This study describes a set of non-peptide, small-molecule Smac (second mitochondria-derived activator of caspases) mimetics that are selective inhibitors of cIAP1/2 over XIAP. The most potent and most selective compounds bind to cIAP1/2 with affinities in the low nanomolar range and show >1,000-fold selectivity for cIAP1 over XIAP. These selective cIAP inhibitors effectively induce degradation of the cIAP1 protein in cancer cells at low nanomolar concentrations and do not antagonize XIAP in a cell-free functional assay. They potently inhibit cell growth and effectively induce apoptosis at low nanomolar concentrations in cancer cells with a mechanism of action similar to that of other known Smac mimetics. Our study shows that binding of Smac mimetics to XIAP BIR3 is not required for effective induction of apoptosis in tumor cells by Smac mimetics. These potent and highly selective cIAP1/2 inhibitors are powerful tools in the investigation of the role of these IAP proteins in the regulation of apoptosis and other cellular processes.

| S-EPMC4324444 | biostudies-literature

Ubiquitin-dependent regulation of MEKK2/3-MEK5-ERK5 signaling module by XIAP and cIAP1.

Project description:Mitogen-activated protein kinases (MAPKs) are highly conserved protein kinase modules, and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-regulated kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or cIAP1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5-dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the physical and functional disassembly of ERK5-MAPK module and human muscle cell differentiation.

| S-EPMC4195761 | biostudies-literature

TRAF2/3 deficient B cells resist DNA damage-induced apoptosis via NF-κB2/XIAP/cIAP2 axis and IAP antagonist sensitizes mutant lymphomas to chemotherapeutic drugs.

Project description:Deletion of TRAF2 or TRAF3 in B cells prolongs their survival. However, it remains unknown whether deletion of such factors affects B cells' ability to tolerate DNA damage, which can be induced by chemotherapeutics and cause apoptosis. Genetic alterations of TRAF2 or TRAF3 are observed in subsets of human B-cell lymphomas and B cell-specific deletion of TRAF3 led to lymphoma development in aged mice. However, it remains unknown whether double deficiency of TRAF2 and TRAF3 accelerates B-cell lymphomagenesis. Here, we showed that B cell-specific TRAF2/3 double deficient (B-TRAF2/3-DKO) B cells were remarkably more resistant to DNA damage-induced apoptosis via upregulating cIAP2 and XIAP, which in turn attenuates caspase-3 activation. Mechanistically, resistance to DNA damage-induced apoptosis required NF-κB2, which effects by upregulating XIAP and cIAP2 transcription. B-TRAF2/3-DKO mice exhibited a shorter lifespan and succumbed to splenomegaly and lymphadenopathy. Unexpectedly, the incidence of B-cell lymphoma development in B-TRAF2/3-DKO mice was relatively rare (∼10%). Sequencing B cell receptor repertoire of diseased B cells revealed that TRAF2/3 deficiency caused abnormal oligoclonal or clonal expansion of B cells. While a fraction of mutant B cells (25-43%) from aged diseased mice harbored recurrent chromosomal translocations, primary B cells isolated from young B-TRAF2/3-DKO mice had no detectable chromosomal alterations, suggesting that TRAF2/3 deficiency per se does not cause evident genomic instability in B cells. Chemo-resistant TRAF3-deficient B-cell lymphomas were sensitized to chemotherapeutic drugs by blocking IAP activity using IAP antagonist. We conclude that double deficiency of TRAF2 and TRAF3 does not accelerate B-cell lymphomagenesis. Our studies provide insight into mechanisms regulating DNA damage-induced apoptosis and may help develop effective therapies targeting mutant B-cell lymphomas using IAP antagonist.

| S-EPMC10485046 | biostudies-literature

Antagonist of cIAP1/2 and XIAP enhances anti-tumor immunity when combined with radiation and PD-1 blockade in a syngeneic model of head and neck cancer.

Project description:Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNF?. Using syngeneic mouse models, ASTX660 showed additive anti-tumor activity with radiation therapy (XRT), cisplatin chemotherapy, and PD-1 blockade to significantly delay or eradicate MOC1 tumors. These combinations significantly increased CD8 + T cells and dendritic cells, as well as T cell activity. ASTX660 stimulated cytotoxic T lymphocyte (CTL) killing of MOC1 cells expressing ovalbumin. Early stages of CTL killing were predominantly mediated by perforin/granzyme B, whereas later stages were mediated by death ligands TNF?, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells in vivo revealed both types of immune cells to be important components of the complete anti-tumor response enhanced by ASTX660+XRT. These findings serve to inform future studies of IAP inhibitors and support the potential for future clinical trials investigating ASTX660 with XRT and immunotherapies like PD-1/PD-L1 blockade in HNSCC.

| S-EPMC6209421 | biostudies-literature

Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-<i>?</i>B signaling by degrading TRAF2-associated cIAP1 in cancer cells.

Project description:The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates. The anti-cellular IAP1 (cIAP1) and pro-apoptotic activities of monovalent IAP antagonists were increased by using a single covalent bond to combine the monovalent moieties at the P4 position. In addition, regardless of drug concentration, treatment with monovalent compounds resulted in consistently higher levels of residual cIAP1 compared with that seen following bivalent compound treatment. We found that the remaining residual cIAP1 following monovalent compound treatment was predominantly tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-associated cIAP1. As a consequence, bivalent compounds were more effective at inhibiting TNF-induced activation of p65/NF-?B compared with monovalent compounds. Moreover, extension of the linker chain at the P4 position of bivalent compounds resulted in a decreased ability to degrade TRAF2-associated cIAP1 in a manner similar to monovalent compounds. This result implied that specific bivalent IAP antagonists but not monovalent compounds were capable of inducing formation of a cIAP1 E3 ubiquitin ligase complex with the capacity to effectively degrade TRAF2-associated cIAP1. These results further suggested that only certain bivalent IAP antagonists are preferred for the targeting of TNF-dependent signaling for the treatment of cancer or infectious diseases.

| S-EPMC5238498 | biostudies-literature

ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer.

Project description:Inhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function. However, tumor-cell-intrinsic mechanisms for this immune upregulation have been largely unexplored. In this study, we show that ASTX660, an antagonist of cIAP1/2 and XIAP, induces expression of immunogenic cell death (ICD) markers in sensitive HNSCC cell lines in vitro. Experiments in syngeneic mouse models of HNSCC showed that ASTX660 can also enhance radiation-induced ICD in vivo. On a functional level, ASTX660 also enhanced killing of multiple murine cell lines by cytotoxic tumor-infiltrating lymphocytes, and when combined with XRT, stimulated clonal expansion of antigen-specific T lymphocytes and expression of MHC class I on the surface of tumor cells. Flow cytometry experiments in several human HNSCC cell lines showed that MHC class I (HLA-A,B,C) was reliably upregulated in response to ASTX660 + TNFα, while increases in other antigen processing machinery (APM) components were variable among different cell lines. These findings suggest that ASTX660 may enhance anti-tumor immunity both by promoting ICD and by enhancing antigen processing and presentation.

| S-EPMC6959437 | biostudies-literature

Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.

Project description:Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit.

| S-EPMC4237265 | biostudies-literature

Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach.

Project description:Recently we reported that rapid determination of enthalpy of binding can be achieved for a large number of congeneric agents or in combinatorial libraries fairly efficiently. We show that using a thermodynamic Craig plot can be very useful in dissecting the enthalpy and entropy contribution of different substituents on a common scaffold, in order to design potent, selective, or pan-active compounds. In our implementation, the approach identified a critical Lys residue in the BIR3 domain of XIAP. We report for the first time that it is possible to target such residue covalently to attain potent and selective agents. Preliminary cellular studies in various models of leukemia, multiple myeloma, and pancreatic cancers suggest that the derived agents possess a potentially intriguing pattern of activity, especially for cell lines that are resistant to the pan-IAP antagonist and clinical candidate LCL161.

| S-EPMC7583350 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data