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Cells
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Regulation of Apoptosis by the Bcl-2 Family of Proteins
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Regulation of Apoptosis by the Bcl-2 Family of Proteins

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 34356

Special Issue Editor

Prof. Alexey S. Ladokhin

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas 66160-7421, USA
Interests: protein–membrane interactions; Bcl-2 proteins; regulation of apoptosis; conformational switching; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The critical step in triggering apoptosis is the permeabilization of the mitochondrial outer membrane (MOMP), which is controlled and executed by the numerous proteins of Bcl-2 family. In spite of the recent advances in solving the structures of the soluble conformations, the exact mechanism of Bcl-2 proteins remains unresolved, primarily because the functionally-important conformations are induced by interactions with the membrane. A major knowledge gap is the lack of accurate molecular pictures of protein–protein and protein–lipid interactions mediating MOMP. This Special Issue seeks reviews and original papers, both experimental and computational, covering a wide range of topics related to structure–function relationships of Bcl-2 proteins, their role in various disorders and their potentials as therapeutic targets.

Prof. Alexey S. Ladokhin
Guest Editor

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Keywords

  • apoptosis
  • mitochondrial outer membrane permeabilization
  • protein-membrane interactions
  • cancer
  • Bcl-2 proteins as therapeutic targets

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 177 KiB  
Editorial
Regulation of Apoptosis by the Bcl-2 Family of Proteins: Field on a Brink
by Alexey S. Ladokhin
Cells 2020, 9(9), 2121; https://doi.org/10.3390/cells9092121 - 18 Sep 2020
Cited by 19 | Viewed by 2159
Abstract
Apoptosis, a form of programmed cell death, is a highly regulated process critical for tissue development, homeostasis, and pathogenesis of various diseases [...] Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)

Research

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15 pages, 3210 KiB  
Article
Conformational Switching in Bcl-xL: Enabling Non-Canonic Inhibition of Apoptosis Involves Multiple Intermediates and Lipid Interactions
by Victor Vasquez-Montes, Alexander Kyrychenko, Mauricio Vargas-Uribe, Mykola V. Rodnin and Alexey S. Ladokhin
Cells 2020, 9(3), 539; https://doi.org/10.3390/cells9030539 - 26 Feb 2020
Cited by 5 | Viewed by 2764
Abstract
The inhibition of mitochondrial permeabilization by the anti-apoptotic protein Bcl-xL is crucial for cell survival and homeostasis. Its inhibitory role requires the partitioning of Bcl-xL to the mitochondrial outer membrane from an inactive state in the cytosol, leading to its extensive refolding. The [...] Read more.
The inhibition of mitochondrial permeabilization by the anti-apoptotic protein Bcl-xL is crucial for cell survival and homeostasis. Its inhibitory role requires the partitioning of Bcl-xL to the mitochondrial outer membrane from an inactive state in the cytosol, leading to its extensive refolding. The molecular mechanisms behind these events and the resulting conformations in the bilayer are unclear, and different models have been proposed to explain them. In the most recently proposed non-canonical model, the active form of Bcl-xL employs its N-terminal BH4 helix to bind and block its pro-apoptotic target. Here, we used a combination of various spectroscopic techniques to study the release of the BH4 helix (α1) during the membrane insertion of Bcl-xL. This refolding was characterized by a gradual increase in helicity due to the lipid-dependent partitioning-coupled folding and formation of new helix αX (presumably in the originally disordered loop between helices α1 and α2). Notably, a comparison of various fluorescence and circular dichroism measurements suggested the presence of multiple Bcl-xL conformations in the bilayer. This conclusion was explicitly confirmed by single-molecule measurements of Förster Resonance Energy Transfer from Alexa-Fluor-488-labeled Bcl-xL D189C to a mCherry fluorescent protein attached at the N-terminus. These measurements clearly indicated that the refolding of Bcl-xL in the bilayer is not a two-state transition and involves multiple membranous intermediates of variable compactness. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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Graphical abstract

13 pages, 2728 KiB  
Article
HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-κB in Cutaneous Squamous Cell Carcinoma
by Shuo Han, Xue Li, Xiaoting Liang and Liang Zhou
Cells 2019, 8(11), 1360; https://doi.org/10.3390/cells8111360 - 31 Oct 2019
Cited by 28 | Viewed by 3476
Abstract
Tumor suppressor HOXA9 has been identified to promote apoptosis in cutaneous squamous cell carcinoma (cSCC). However, the mechanism of such pro-apoptotic role of HOXA9 remains obscure. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data showed that NF-κB, apoptosis and autophagy [...] Read more.
Tumor suppressor HOXA9 has been identified to promote apoptosis in cutaneous squamous cell carcinoma (cSCC). However, the mechanism of such pro-apoptotic role of HOXA9 remains obscure. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data showed that NF-κB, apoptosis and autophagy pathways are significantly regulated after HOXA9 knockdown. HOXA9 transcriptionally regulates RELA, the p65 subunit of NF-κB. Loss of HOXA9 in cSCC significantly upregulates RELA expression and thus enhances NF-κB pathway. Interestingly, RELA transcriptionally promotes not only anti-apoptotic factor BCL-XL but also autophagic genes including ATG1, ATG3, and ATG12. Our results reveal an enhanced NF-κB signaling network regulated by HOXA9, which contributes to repressed apoptosis and activated autophagy in cSCC development and may represent an intervention target for cSCC therapy. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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Graphical abstract

13 pages, 4002 KiB  
Article
The Deubiquitinating Enzyme Inhibitor PR-619 Enhances the Cytotoxicity of Cisplatin via the Suppression of Anti-Apoptotic Bcl-2 Protein: In Vitro and In Vivo Study
by Kuan-Lin Kuo, Shing-Hwa Liu, Wei-Chou Lin, Po-Ming Chow, Yu-Wei Chang, Shao-Ping Yang, Chung-Sheng Shi, Chen-Hsun Hsu, Shih-Ming Liao, Hong-Chiang Chang and Kuo-How Huang
Cells 2019, 8(10), 1268; https://doi.org/10.3390/cells8101268 - 17 Oct 2019
Cited by 20 | Viewed by 4534
Abstract
After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor [...] Read more.
After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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Review

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25 pages, 3244 KiB  
Review
Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer
by Simona D’Aguanno and Donatella Del Bufalo
Cells 2020, 9(5), 1287; https://doi.org/10.3390/cells9051287 - 21 May 2020
Cited by 91 | Viewed by 7744
Abstract
The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small [...] Read more.
The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small molecules able to target anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1. The limitations of the first Bcl-2 family targeted drugs, regarding on-target and off-target toxicities, have been overcome with the development of venetoclax (ABT-199), the first BH3 mimetic inhibitor approved by the FDA. The purpose of this review is to discuss the state-of-the-art in the development of drugs targeting Bcl-2 anti-apoptotic proteins and to highlight the potential of their application as single agents or in combination for improving anti-cancer therapy, focusing in particular on solid tumors. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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15 pages, 1120 KiB  
Review
Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies
by Maxime Jullien, Patricia Gomez-Bougie, David Chiron and Cyrille Touzeau
Cells 2020, 9(3), 717; https://doi.org/10.3390/cells9030717 - 14 Mar 2020
Cited by 16 | Viewed by 4768
Abstract
Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-XL) is a common [...] Read more.
Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-XL) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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Other

10 pages, 955 KiB  
Perspective
The Incomplete Puzzle of the BCL2 Proteins
by Hector Flores-Romero and Ana J. García-Sáez
Cells 2019, 8(10), 1176; https://doi.org/10.3390/cells8101176 - 29 Sep 2019
Cited by 33 | Viewed by 7882
Abstract
The proteins of the BCL2 family are key players in multiple cellular processes, chief amongst them being the regulation of mitochondrial integrity and apoptotic cell death. These proteins establish an intricate interaction network that expands both the cytosol and the surface of organelles [...] Read more.
The proteins of the BCL2 family are key players in multiple cellular processes, chief amongst them being the regulation of mitochondrial integrity and apoptotic cell death. These proteins establish an intricate interaction network that expands both the cytosol and the surface of organelles to dictate the cell fate. The complexity and unpredictability of the BCL2 interactome resides in the large number of family members and of interaction surfaces, as well as on their different behaviours in solution and in the membrane. Although our current structural knowledge of the BCL2 proteins has been proven therapeutically relevant, the precise structure of membrane-bound complexes and the regulatory effect that membrane lipids exert over these proteins remain key questions in the field. Here, we discuss the complexity of BCL2 interactome, the new insights, and the black matter in the field. Full article
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
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