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Search results for: CIAP1 BIRC2

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#32719312   2020/07/27 To Up

SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages.

Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.
Grant R Campbell, Rachel K To, Gang Zhang, Stephen A Spector

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#31266830   2019/07/02 To Up

Dual Antagonist of cIAP/XIAP ASTX660 Sensitizes HPV and HPV Head and Neck Cancers to TNFα, TRAIL, and Radiation Therapy.

Human papillomavirus-negative (HPV) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV, but not HPV tumors, to TNF family death ligands (TNF and TRAIL) and radiation. We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV and HPV cell lines in combination with death ligands TNFα and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion.
Roy Xiao, Yi An, Wenda Ye, Adeeb Derakhshan, Hui Cheng, Xinping Yang, Clint Allen, Zhong Chen, Nicole C Schmitt, Carter Van Waes

2323 related Products with: Dual Antagonist of cIAP/XIAP ASTX660 Sensitizes HPV and HPV Head and Neck Cancers to TNFα, TRAIL, and Radiation Therapy.

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#31217499   2019/06/19 To Up

PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1.

Most deaths from breast cancer result from tumour recurrence, which is typically an incurable disease. Down-regulation of the pro-apoptotic tumour suppressor protein prostate apoptosis response-4 (PAR-4) is required for breast cancer recurrence and resistance to chemotherapy. Recent advances in the analysis of apoptotic signalling networks have uncovered an important role for activation of caspase-8 following DNA damage by genotoxic drugs. DNA damage induces depletion of IAP proteins and causes caspase-8 activation by promoting the formation of a cytosolic cell death complex. We demonstrate that loss of PAR-4 in triple negative breast cancer cell lines (TNBC) mediates resistance to DNA damage-induced apoptosis and prevents activation of caspase-8. Moreover, loss of PAR-4 prevents DNA damage-induced cIAP1 depletion. PAR-4 functions downstream of caspase-8 by cleavage-induced nuclear translocation of the C-terminal part and we demonstrate that nuclear translocation of the C-terminal PAR-4 fragment leads to depletion of cIAP1 and subsequent caspase-8 activation. Specifically targeting cIAP1 with RNAi or Smac mimetics (LCL161) overcomes chemo-resistance induced by loss of PAR-4 and restores caspase-8 activation. Our data identify cIAP1 as important downstream mediator of PAR-4 and we provide evidence that combining Smac mimetics and genotoxic drugs creates vulnerability for synthetic lethality in TNBC cells lacking PAR-4.
Haihong Guo, Fabian Treude, Oliver H Krämer, Bernhard Lüscher, Jörg Hartkamp

2627 related Products with: PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1.

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#31049403   2019/05/01 To Up

cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T.

IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of T17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human T subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4 IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in T and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between T17 and T and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.
Joanna Z Kawalkowska, Joy Ogbechi, Patrick J Venables, Richard O Williams

2706 related Products with: cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T.

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#31015310   2019/04/23 To Up

LCL161, a SMAC-mimetic, Preferentially Radiosensitizes Human Papillomavirus-negative Head and Neck Squamous Cell Carcinoma.

Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus-positive (HPV) and -negative (HPV) HNSCC. The association of (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV compared with HPVHNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues ( = 0.0003) and associated with a poor overall survival ( = 0.0402). cIAP1 levels were higher in HPV than that in HPVHNSCC tumors ( = 0.004) and patients with cIAP1/HPV HNSCC had the worst survival. LCL161 effectively radiosensitized HPV HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV HNSCC.
Linlin Yang, Bhavna Kumar, Changxian Shen, Songzhu Zhao, Dukagjin Blakaj, Tianyun Li, Mitchell Romito, Theodoros N Teknos, Terence M Williams

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#30784599   // To Up

Absence of Cytosolic 2-Cys Prx Subtypes I and II Exacerbates TNF-α-Induced Apoptosis via Different Routes.

There are abundant peroxiredoxin (Prx) enzymes, but an increase of cellular HO level always happens in apoptotic cells. Here, we show that cellular HO switches different apoptosis pathways depending on which type of Prx enzyme is absent. TNF-α-induced HO burst preferentially activates the DNA damage-dependent apoptosis pathway in the absence of PrxI. By contrast, the same HO burst stimulates the RIPK1-dependent apoptosis pathway in the absence of PrxII by inducing the destruction of cIAP1 in caveolar membrane. Specifically, HO induces the oxidation of Cys308 residue in the cIAP1-BIR3 domain, which induces the dimerization-dependent E3 ligase activation. Thus, the reduction in cIAP level by the absence of PrxII triggers cell-autonomous apoptosis in cancer cells and tumors. Such differential functions of PrxI and PrxII are mediated by interaction with H2AX and cIAP1, respectively. Collectively, this study reveals the distinct switch roles of 2-Cys Prx isoforms in apoptosis signaling.
Sunmi Lee, Joo Young Lee, Eun Woo Lee, Sujin Park, Dong Hoon Kang, Chengchun Min, Doo Jae Lee, Dongmin Kang, Jaewhan Song, Jongbum Kwon, Sang Won Kang

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#30761457   2019/02/13 To Up

Overexpression of apoptosis-related protein, survivin, in fibroblasts from patients with systemic sclerosis.

Recent studies suggest that, in addition to activation and hypersecretion of matrix components, fibroblasts from patients with systemic sclerosis (SSc) are resistant to apoptosis. Previous studies have shown that survivin, a member of inhibition of apoptosis (IAP) family, plays an important role in apoptosis resistance. Accordingly, we decided to study the expression of the most important members of IAP family in SSc fibroblasts, which can block apoptosis either by binding and inhibiting caspases or through caspase-independent mechanisms.
Mohammad Bagher Mahmoudi, Ehsan Farashahi Yazd, Farhad Gharibdoost, Mohammad Hasan Sheikhha, Elham Karimizadeh, Ahmadreza Jamshidi, Mahdi Mahmoudi

1571 related Products with: Overexpression of apoptosis-related protein, survivin, in fibroblasts from patients with systemic sclerosis.

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#30393585   2018/08/01 To Up

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.

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 TNFα. 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 TNFα, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells 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.
Roy Xiao, Clint T Allen, Linda Tran, Priya Patel, So-Jin Park, Zhong Chen, Carter Van Waes, Nicole C Schmitt

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#30359437   2018/10/25 To Up

E2F1 binds to the peptide-binding groove within the BIR3 domain of cIAP1 and requires cIAP1 for chromatin binding.

The cellular inhibitor of apoptosis 1 (cIAP1) is an E3-ubiquitin ligase that regulates cell signaling pathways involved in fundamental cellular processes including cell death, cell proliferation, cell differentiation and inflammation. It recruits ubiquitination substrates thanks to the presence of three baculoviral IAP repeat (BIR) domains at its N-terminal extremity. We previously demonstrated that cIAP1 promoted the ubiquitination of the E2 factor 1 (E2F1) transcription factor. Moreover, we showed that cIAP1 was required for E2F1 stabilization during the S phase of cell cycle and in response to DNA damage. Here, we report that E2F1 binds within the cIAP1 BIR3 domain. The BIR3 contains a surface hydrophobic groove that specifically anchors a conserved IAP binding motif (IBM) found in a number of intracellular proteins including Smac. The Smac N-7 peptide that includes the IBM, as well as a Smac mimetic, competed with E2F1 for interaction with cIAP1 demonstrating the importance of the BIR surface hydrophobic groove. We demonstrated that the first alpha-helix of BIR3 was required for E2F1 binding, as well as for the binding of Smac and Smac mimetics. Overexpression of cIAP1 modified the ubiquitination profile of E2F1, increasing the ratio of E2F1 conjugated with K11- and K63-linked ubiquitin chains, and decreasing the proportion of E2F1 modified by K48-linked ubiquitin chains. ChIP-seq analysis demonstrated that cIAP1 was required for the recruitment of E2F1 onto chromatin. Lastly, we identified an E2F-binding site on the cIAP1-encoding birc2 gene promoter, suggesting a retro-control regulation loop.
Jennifer Allègre, Jessy Cartier, Valérie Glorian, Nathalie Droin, Baptiste Dumetier, Cémile Kayaci, Jean Berthelet, Simon Gemble, Céline Vuillier, Laurent Maillet, Carmen Garrido, Laurence Dubrez

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#30344003   2018/10/18 To Up

SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells.

Long-lived resting memory CD4+ T cells (T) are a major reservoir of latent HIV infection. We hypothesized that latent HIV-T cells are maintained by aberrant expression of cell survival factors, including XIAP, BIRC2/cIAP1, and beclin-1. DIABLO/SMAC mimetics are therapeutic agents that compromise cell survival by hijacking host apoptotic machinery. We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-T without increasing virus production or targeting uninfected T. Treatment of HIV-T with DIABLO/SMAC mimetics promoted XIAP and BIRC2 degradation, which triggered autophagy and the formation of a cell death complex consisting of pro-apoptotic (FADD, RIPK1, RIPK3, and caspase 8) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-T without viral reactivation while sparing uninfected cells.
Grant R Campbell, Rachel S Bruckman, Yen-Lin Chu, Rodney N Trout, Stephen A Spector

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