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MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells.

ABSTRACT: Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial-Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.

SUBMITTER: Pratelli G

PROVIDER: S-EPMC10342057 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells.

Pratelli Giovanni G Carlisi Daniela D Di Liberto Diana D Notaro Antonietta A Giuliano Michela M D'Anneo Antonella A Lauricella Marianna M Emanuele Sonia S Calvaruso Giuseppe G De Blasio Anna A

International journal of molecular sciences 20230706 13

Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial-Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA ...[more]

PMID: 37446326

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Project description:Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

Project description:Natural killer cells (NK cells) are essential in cancer immunosurveillance in the body as they can recognize cancer cells that lacking MHC class 1 on their surface. Regulatory cytokines, including interleukin (IL)-18, IL-12, IL-10, IL-8, interferon-γ (IFN-γ), and secretory granules like perforin and granzyme are involved in NK cell-mediated cytotoxicity. Stimulating NK cells cytotoxicity towards cancer cells is an ideal strategy to combat cancer naturally. Medicinal plants have been reported to enhance immunity, with Pereskia bleo (P. bleo) particularly noteworthy due to its abundant bioactive compounds and ability to activate immune cells. This study aimed to evaluate the potential of methanol extract of P. bleo leaves (MEPB) for enhancing NK cell cytotoxicity against triple-negative human breast cancer cells (MDA-MB-231). The optimal concentration of MEPB to activate NK cells was determined using healthy blood samples, assessing the expression of IL-12, IL-18, IL-10, IL-8, IFN-γ, perforin, and granzyme B via an enzyme-linked immunosorbent assay (ELISA). NK cell purity from healthy donors and breast cancer patients was determined using specific antibodies, and the number of NK cells was assessed using flow cytometry and a hemocytometer. A co-culture experiment, ELISA, and apoptosis assay were used to evaluate NK-mediated cytotoxicity pathways. ELISA data indicated that MEPB at 7.5 µg/ml significantly increased the expression of IFN-γ, IL-12, IL-18, perforin, and granzyme B while decreasing IL-8 and IL-10 expression after 20 hrs of incubation. The average NK cell purity was 87.09 ± 0.043%. Breast cancer patients exhibited lower NK cell counts than healthy donors. Co-culture experiments demonstrated that NK cells induced apoptosis in MDA-MB-231 breast cancer cells in the presence of MEPB by increasing perforin, granzyme B, and IFN-γ expression in both healthy donors and breast cancer patients-experimental groups. P. bleo enhances NK cell activation, promoting the apoptosis of triple-negative human breast cancer cells (MDA-MB-231), suggesting the potential use of MEPB leaves as an anti-cancer immunostimulant.

Dataset Information

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells.

Publications

MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells.

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