ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Mechanisms of MCL-1 Protein Stability Induced by MCL-1 Antagonists in B-Cell Malignancies.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Atractylenolide I alleviates LPS-induced pulmonary cell injury relevant to pediatric pneumonia via the ERK/USP9X/Mcl-1 and Akt/Survivin axes.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- GET3 regulates apoptosis via tail-anchoring of MCL1.Cell death and differentiation · 2026Article
- Dioscin suppresses tumorigenesis and overcomes radioresistance by promoting ubiquitination-mediated degradation of Mcl-1.Cancer gene therapy · 2026Article
- PROTAC-mediated degradation of Bcl-xL potentiates target therapy in preclinical melanoma models.Journal of experimental & clinical cancer research : CR · 2026Article
- Multiplex design and discovery of proximity handles for programmable proteome editing.bioRxiv : the preprint server for biology · 2025Article
- Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality.Health science reports · 2025Article
- Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.Molecular cancer therapeutics · 2025Article
- A new era in cancer therapy: targeting the Proteasome-Bcl-2 axis.Journal of experimental & clinical cancer research : CR · 2025Review
- Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity.Cancer gene therapy · 2025Article
- (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.Scientific reports · 2025Article
- Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia.Signal transduction and targeted therapy · 2025Article
- Multidimensional, integrative profiling identifies BCL2L1 methylation as a predictor of MCL1 dependency in pediatric malignancies.JCI insight · 2025Article
- Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xInternational journal of molecular sciences · 2024Article
- Mcl-1 Protein and Viral Infections: A Narrative Review.International journal of molecular sciences · 2024Review
- Review
- Decoding the mechanism behind MCL-1 inhibitors: A pathway to understanding MCL-1 protein stability.Oncotarget · 2023Article
- AMG176, an MCL-1 inhibitor, is active in pre-clinical models of aggressive B-cell lymphomas.Leukemia & lymphoma · 2023Article
- Targeting MCL-1 protein to treat cancer: opportunities and challenges.Frontiers in oncology · 2023Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeSeveral MCL-1 inhibitors (MCL-1i), including AMG-176 and AZD5991, have shown promise in preclinical studies and are being tested for the treatment of hematologic malignancies. A unique feature of these agents is induction and stability of Mcl-1 protein; however, the precise mechanism is unknown. We aim to study the mechanism of MCL-1i-induced Mcl-1 protein stability. EXPERIMENTAL
designUsing several B-cell leukemia and lymphoma cell lines and primary chronic lymphocytic leukemia (CLL) lymphocytes, we evaluated molecular events associated with Mcl-1 protein stability including protein half-life, reverse-phase protein array, protein-protein interaction, phosphorylation, ubiquitination, and de-ubiquitination, followed by molecular simulation and modeling.
resultsUsing both in vivo and in vitro analysis, we demonstrate that MCL-1i-induced Mcl-1 protein stability is predominantly associated with defective Mcl-1 ubiquitination and concurrent apoptosis induction in both cell lines and primary CLL subjects. These MCL1i also induced ERK-mediated Mcl-1Thr163 phosphorylation, which partially contributed to Mcl-1 stability. Disruption of Mcl-1:Noxa interaction followed by Noxa degradation, enhanced Mcl-1 de-ubiquitination by USP9x, and Mule destabilization are the major effects of these inhibitors. However, unlike other BH3 proteins, Mule:Mcl-1 interaction was unaffected by MCL-1i. WP1130, a global deubiquitinase (DUB) inhibitor, abrogated Mcl-1 induction reaffirming a critical role of DUBs in the observed Mcl-1 protein stability. Further, in vitro ubiquitination studies of Mcl-1 showed distinct difference among these inhibitors.
conclusionsWe conclude that MCL-1i blocked Mcl-1 ubiquitination via enhanced de-ubiquitination and dissociation of Mcl-1 from Noxa, Bak and Bax, and Mule de-stabilization. These are critical events associated with increased Mcl-1 protein stability with AMG-176 and AZD5991.
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