scholarly journals Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 663 ◽  
Author(s):  
Ruqaia Abbas ◽  
Sarit Larisch
Keyword(s):  
Cell Death ◽  
Ubiquitin Proteasome System ◽  
Cancer Therapies ◽  
Apoptotic Pathway ◽  
Cancer Cell Death ◽  
Iap Antagonist ◽  
Smac Mimetics ◽  
Smac Mimetic ◽  
Ubiquitin Proteasome ◽  
Regulate Cell Death

Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP.

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

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Grant R. Campbell ◽  
Rachel K. To ◽  
Gang Zhang ◽  
Stephen A. Spector
Keyword(s):  
Cell Death ◽  
Hiv Infection ◽  
Cell Survival ◽  
Acute Hiv Infection ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Hiv Eradication ◽  
Smac Mimetics ◽  
Smac Mimetic ◽  
Latent Hiv

Abstract 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.

scholarly journals Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

2019 ◽  
Vol 27 (5) ◽  
pp. 1569-1587 ◽  
Author(s):  
Jing Zhang ◽  
Yu Yang ◽  
Shen’ao Zhou ◽  
Xueyan He ◽  
Xuan Cao ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Tumor Regression ◽  
Cell Types ◽  
Tight Contact ◽  
Cancer Cell Death ◽  
Microtubule Targeting Agents ◽  
Patient Responsiveness ◽  
Smac Mimetics

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

scholarly journals HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Maxime J Kinet ◽  
Jennifer A Malin ◽  
Mary C Abraham ◽  
Elyse S Blum ◽  
Melanie R Silverman ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Ubiquitin Proteasome System ◽  
Mitogen Activated Protein Kinase ◽  
Death Process ◽  
Heat Shock Factor 1 ◽  
Vertebrate Development ◽  
C Elegans ◽  
Ubiquitin Proteasome ◽  
Developmental Cell Death

Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65

2012 ◽  
Vol 443 (3) ◽  
pp. 681-689 ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Hon Wing Luk ◽  
Ho Yin Edwin Chan ◽  
Kwok-Fai Lau
Keyword(s):  
Cell Death ◽  
Degradation Mechanism ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Ubiquitin Proteasome System ◽  
Exon 1 ◽  
Ubiquitin Proteasome

An unstable expansion of the polyglutamine repeat within exon 1 of the protein Htt (huntingtin) causes HD (Huntington's disease). Mounting evidence shows that accumulation of N-terminal mutant Htt fragments is the source of disruption of normal cellular processes which ultimately leads to neuronal cell death. Understanding the degradation mechanism of mutant Htt and improving its clearance has emerged as a new direction in developing therapeutic approaches to treat HD. In the present study we show that the brain-enriched adaptor protein FE65 is a novel interacting partner of Htt. The binding is mediated through WW–polyproline interaction and is dependent on the length of the polyglutamine tract. Interestingly, a reduction in mutant Htt protein level was observed in FE65-knockdown cells, and the process requires the UPS (ubiquitin/proteasome system). Moreover, the ubiquitination level of mutant Htt was found to be enhanced when FE65 is knocked down. Immunofluroescence staining revealed that FE65 associates with mutant Htt aggregates. Additionally, we demonstrated that overexpression of FE65 increases mutant Htt-induced cell death both in vitro and in vivo. These results suggest that FE65 facilitates the accumulation of mutant Htt in cells by preventing its degradation via the UPS, and thereby enhances the toxicity of mutant Htt.

Amelioration of neuronal cell death in a spontaneous obese rat model by dietary restriction through modulation of ubiquitin proteasome system

2016 ◽  
Vol 33 ◽  
pp. 73-81 ◽  
Author(s):  
Karnam Shruthi ◽  
S. Sreenivasa Reddy ◽  
P. Yadagiri Reddy ◽  
Potula Shivalingam ◽  
Nemani Harishankar ◽  
...  
Keyword(s):  
Cell Death ◽  
Dietary Restriction ◽  
Rat Model ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome
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