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Biomolecules
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BCL-2 Family in Health and Diseases
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BCL-2 Family in Health and Diseases

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 28593

Special Issue Editor

Prof. Germain Gillet

E-Mail Website
Guest Editor
Centre de Recherche en Cancérologie de Lyon, Lyon, France
Interests: role of Bcl-2 family proteins in development and tumor progression; molecular mechanisms underlying the non canonical functions of Bcl-2 proteins; including Ca2+ homeostasis and cell movements; in the context of breast cancer and vertebrate development

Special Issue Information

Dear Colleagues,

Bcl-2 family proteins are the gatekeepers of mitochondria integrity and the main regulators of apoptosis. They contribute to the balance between cell proliferation and cell death and are thus critical for cell homeostasis. Besides the control of apoptosis, non-canonical functions of Bcl-2 proteins have recently been described, including the control of the cell cycle, cell differentiation, axonal growth, redox status and metabolism as well as calcium trafficking. How these different functions are integrated remains largely unknown.  In the context of cancer, upregulation of anti-apoptotic Bcl-2 homologs is often correlated with resistance to chemotherapy and poor prognosis. Regarding subcellular localization, targeting mitochondria-addressed Bcl-2 proteins appears to be a promising approach for the design of novel anticancer therapies. However, targeting endoplasmic reticulum-based Bcl-2 proteins was recently found to be an alternative strategy. In fact, there is increasing evidence that the distribution of Bcl-2 proteins inside the cell is a dynamic process which is profoundly affected by changes in the cellular microenvironment. Thus, investigating the mechanisms that underlie the multiple roles of this fascinating family of proteins, is expected to open up new research avenues, which are expected to have major implications in the clinic.

This Special Issue welcomes manuscripts dealing with the numerous facets of Bcl-2 family proteins, from structural biology to clinical implications. Apart from their role in the mitochondrial pathway of apoptosis, manuscripts dealing with non-apoptotic roles of Bcl-2 proteins are encouraged.

Prof. Germain Gillet
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Development
  • Stress
  • Cancer
  • Degenerative diseases
  • Mitochondria and other subcellular compartments
  • Interaction domains, including Bcl-2 homology domains
  • Protein-membrane interactions
  • Calcium trafficking
  • Cell migration and differentiation
  • Metabolism
  • Bcl-2 inhibitors, including peptides and small molecules

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Published Papers (4 papers)

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Research

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13 pages, 2714 KiB  
Article
DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition
by Martijn Kerkhofs, Tamara Vervloessem, Kinga B. Stopa, Victoria M. Smith, Meike Vogler and Geert Bultynck
Biomolecules 2020, 10(7), 1081; https://doi.org/10.3390/biom10071081 - 21 Jul 2020
Cited by 11 | Viewed by 3904
Abstract
Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax [...] Read more.
Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax. Full article
(This article belongs to the Special Issue BCL-2 Family in Health and Diseases)
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Review

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14 pages, 17942 KiB  
Review
The Mysteries around the BCL-2 Family Member BOK
by Raed Shalaby, Hector Flores-Romero and Ana J. García-Sáez
Biomolecules 2020, 10(12), 1638; https://doi.org/10.3390/biom10121638 - 4 Dec 2020
Cited by 17 | Viewed by 3830
Abstract
BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of [...] Read more.
BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions. Full article
(This article belongs to the Special Issue BCL-2 Family in Health and Diseases)
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24 pages, 1595 KiB  
Review
Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?
by Sophie Barillé-Nion, Steven Lohard and Philippe P. Juin
Biomolecules 2020, 10(8), 1109; https://doi.org/10.3390/biom10081109 - 25 Jul 2020
Cited by 7 | Viewed by 5757
Abstract
The imbalance between BCL-2 homologues and pro-death counterparts frequently noted in cancer cells endows them with a cell autonomous survival advantage. To eradicate ectopic cells, inhibitors of these homologues (BH3 mimetics) were developed to trigger, during anticancer treatment, full activation of the canonical [...] Read more.
The imbalance between BCL-2 homologues and pro-death counterparts frequently noted in cancer cells endows them with a cell autonomous survival advantage. To eradicate ectopic cells, inhibitors of these homologues (BH3 mimetics) were developed to trigger, during anticancer treatment, full activation of the canonical mitochondrial apoptotic pathway and related caspases. Despite efficiency in some clinical settings, these compounds do not completely fulfill their initial promise. We herein put forth that a growing body of evidence indicates that mitochondrial integrity, controlled by BCL-2 family proteins, and downstream caspases regulate other cell death modes and influence extracellular signaling by committed cells. Moreover, intercellular communications play a key role in spreading therapeutic response across cancer cell populations and in engaging an immune response. We thus advocate that BH3 mimetics administration would be more efficient in the long term if it did not induce apoptosis in all sensitive cells at the same time, but if it could instead allow (or trigger) death signal production by non-terminally committed dying cell populations. The development of such a trade-off strategy requires to unravel the effects of BH3 mimetics not only on each individual cancer cell but also on homotypic and heterotypic cell interactions in dynamic tumor ecosystems. Full article
(This article belongs to the Special Issue BCL-2 Family in Health and Diseases)
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21 pages, 2653 KiB  
Review
The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms
by Suresh Banjara, Chathura D. Suraweera, Mark G. Hinds and Marc Kvansakul
Biomolecules 2020, 10(1), 128; https://doi.org/10.3390/biom10010128 - 12 Jan 2020
Cited by 98 | Viewed by 14422
Abstract
Intrinsic apoptosis, the response to intracellular cell death stimuli, is regulated by the interplay of the B-cell lymphoma 2 (Bcl-2) family and their membrane interactions. Bcl-2 proteins mediate a number of processes including development, homeostasis, autophagy, and innate and adaptive immune responses and [...] Read more.
Intrinsic apoptosis, the response to intracellular cell death stimuli, is regulated by the interplay of the B-cell lymphoma 2 (Bcl-2) family and their membrane interactions. Bcl-2 proteins mediate a number of processes including development, homeostasis, autophagy, and innate and adaptive immune responses and their dysregulation underpins a host of diseases including cancer. The Bcl-2 family is characterized by the presence of conserved sequence motifs called Bcl-2 homology motifs, as well as a transmembrane region, which form the interaction sites and intracellular location mechanism, respectively. Bcl-2 proteins have been recognized in the earliest metazoans including Porifera (sponges), Placozoans, and Cnidarians (e.g., Hydra). A number of viruses have gained Bcl-2 homologs and subvert innate immunity and cellular apoptosis for their replication, but they frequently have very different sequences to their host Bcl-2 analogs. Though most mechanisms of apoptosis initiation converge on activation of caspases that destroy the cell from within, the numerous gene insertions, deletions, and duplications during evolution have led to a divergence in mechanisms of intrinsic apoptosis. Currently, the action of the Bcl-2 family is best understood in vertebrates and nematodes but new insights are emerging from evolutionarily earlier organisms. This review focuses on the mechanisms underpinning the activity of Bcl-2 proteins including their structures and interactions, and how they have changed over the course of evolution. Full article
(This article belongs to the Special Issue BCL-2 Family in Health and Diseases)
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