IAP Proteins Antagonist: An Introduction and Chemistry of Smac Mimetics under Clinical Development

Ali, Rafat; Singh, Shalini; Haq, W.

doi:10.2174/0929867325666180313112229

Cited by 13 publications

(13 citation statements)

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“…Several studies have shown that overexpression of SMAC/DIABLO can sensitize cancer cells to apoptosis, thus the development of small-molecule SMAC mimetics has been an attractive goal for cancer treatment in the last decade [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

Mariniello

Orlandella

Stefano

et al. 2020

IJMS

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Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma.

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Section: Discussionmentioning

confidence: 99%

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

Mariniello

Orlandella

Stefano

et al. 2020

IJMS

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“…In brief, as a result of either low level or dysfunction, the activity of SMAC decreases in cancer cells, rendering it unable to antagonize the upregulated IAPs. Thus, SMs, also known as IAP antagonists, which are a new class of targeted drugs to suppress the IAPs, came into view [63].…”

Section: Depression Of Smac Activity Due To Overexpression Of Iapsmentioning

confidence: 99%

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Zhao

Wang

Wei

et al. 2020

Cells

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Aiming to promote cancer cell apoptosis is a mainstream strategy of cancer therapy. The second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) protein is an essential and endogenous antagonist of inhibitor of apoptosis proteins (IAPs). SMAC mimetics (SMs) are a series of synthetically chemical compounds. Via database analysis and literature searching, we summarize the potential mechanisms of endogenous SMAC inefficiency, degradation, mutation, releasing blockage, and depression. We review the development of SMs, as well as preclinical and clinical outcomes of SMs in solid tumor treatment, and we analyze their strengths, weaknesses, opportunities, and threats from our point of view. We also highlight several questions in need of further investigation.

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“…However, when AREL1 is present, SMAC is ubiquitylated by AREL1 and degraded, thus blocking SMAC-cIAP1/2 complex formation enabling cell survival [33]. Many cancer therapies are interested in specifically turning on apoptosis through IAPs in cancer cells [47][48][49], Figure 1. AREL1 domain architecture.…”

Section: Arel1 a Key Regulator Of Apoptosis And Potential Oncogenic mentioning

confidence: 99%

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

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IAP Proteins Antagonist: An Introduction and Chemistry of Smac Mimetics under Clinical Development

Cited by 13 publications

References 0 publications

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

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