Cysteine-linked dimerization of BST-2 confers anoikis resistance to breast cancer cells by negating proapoptotic activities to promote tumor cell survival and growth

Mahauad‐Fernandez, Wadie D.; Okeoma, Chioma M.

doi:10.1038/cddis.2017.68

Cited by 24 publications

(58 citation statements)

References 38 publications

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“…In addition, it has been suggested that increased immune cell adhesion and resistance of cancer cells to tamoxifen-induced apoptosis is linked to BST-2 expression [27,28,30]. We have also shown that the silencing of BST-2 in murine and human breast cancer cell lines results in a shift from a highly aggressive to a non-aggressive phenotype, including loss of cell to cell and cell to ECM adhesion [24,29], decrease in anchorage-independent growth/survival, formation of invadopodia for ECM remodeling, migration, and invasion [31]. Together, these findings suggest a potential for BST-2 as a valuable therapeutic target.…”

Section: Introductionmentioning

confidence: 68%

“…It has been previously shown that B49 and B49Mod1 possess anti-adhesion activity [32]. Since B49Mod1 contains cysteine residues that mediate BST-2 dimerization [12][13][14] and the adhesion-promoting function of BST-2 [29], we examined the role of cysteine-linked disulfide (S-S) bonds in the anti-adhesion function of B49Mod1. 2 mol equivalents of 1,4-Dithiothreitol (DTT), a reducing agent that reversibly breaks down protein S-S was added to B49Mod1 without quenching the oxidative process followed by incubation at 56 • C for 30 minutes.…”

Section: Cysteine-linked Disulfide Bond Is Important For Anti-adhesiomentioning

confidence: 99%

“…Findings from many labs have shown that BST-2 is overexpressed in several cancers including lung cancer [17], head and neck carcinomas [18], oral cavity cancers [19], glioblastomas [20], endometrial cancer [21], lymphomas [22], and breast cancer [23,24]. In breast cancer cells, elevated levels of BST-2 have been associated with increased cancer cell migration [24][25][26], invasion [24,26,27], adhesion, and resistance to apoptosis/anoikis [28,29]. In addition, it has been suggested that increased immune cell adhesion and resistance of cancer cells to tamoxifen-induced apoptosis is linked to BST-2 expression [27,28,30].…”

Section: Introductionmentioning

confidence: 99%

“…The aim of the present study was to use sequence/structure modification and bioactivity guided separation of B49Mod1 to develop a shorter B49Mod1 analog. Based on the structural information of B49Mod1, which contains three cysteine residues (9CYS, 19CYS, 47CYS, corresponding to 53CYS, 63CYS, and 91CYS in BST-2) and the importance of the BST-2 ECD cysteine residues, especially 91CYS, on cancer cell adhesion [29], we used trypsin-mediated degradation studies to truncate B49Mod1 into six smaller fragments as the first step of the structure-activity relationship (SAR) studies. Three of the predicted B49Mod1 peptide fragments that contain cysteine residues were synthesized.…”

Section: Introductionmentioning

confidence: 99%

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Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

2020

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Inhibition of cancer cell adhesion is an effective approach to killing adherent cancer cells. B49 and its analog B49Mod1 peptides, derived from the extracellular domain (ECD) of bone marrow stromal antigen 2 (BST-2), display anti-adhesion activity on breast cancer cells. However, the minimal sequence required for this anti-adhesion activity is unknown. Here, we further characterized the anti-adhesion activity of B49Mod1. We show that the anti-adhesion activity of B49Mod1 may require cysteine-linked disulfide bond and that the peptide is susceptible to proteolytic deactivation. Using structure-activity relationship studies, we identified an 18-Mer sequence (B18) as the minimal peptide sequence mediating the anti-adhesion activity of B49Mod1. Atomistic molecular dynamic (MD) simulations reveal that B18 forms a stable complex with the ECD of BST-2 in aqueous solution. MD simulations further reveal that B18 may cause membrane defects that facilitates peptide translocation across the bilayer. Placement of four B18 chains as a transmembrane bundle results in water channel formation, indicating that B18 may impair membrane integrity and form pores. We hereby identify B18 as the minimal peptide sequence required for the anti-adhesion activity of B49Mod1 and provide atomistic insight into the interaction of B18 with BST-2 and the cell membrane.

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Section: Introductionmentioning

confidence: 68%

Section: Cysteine-linked Disulfide Bond Is Important For Anti-adhesiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

2020

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“…Recently, a tumorigenic role of BST2 has been suggested although the mechanism has not been completely clarified. In breast cancer cells, BST-2 mediates cancer cell adhesion and anchorage-independent growth thereby promoting tumor cell survival through inhibition of anoikis [53]. In vascular endothelial cells, IFNγ-induced up-regulation of BST2 mediates adhesion to monocytes [54].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Tumor-Lymphatic Interactions in Invasive Breast and Prostate Carcinoma

Oliveira‐Ferrer

Milde‐Langosch

Eylmann

et al. 2020

IJMS

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During the last few years, diverse studies have shown that tumors can actively interact with the lymphatic system and promote metastases development. In order to examine the molecular mechanisms involved in this interaction, we co-cultured tumor and lymphatic endothelial cells (LEC) and subsequently analyzed the molecular alterations of LECs. Therefore, LECs were co-cultivated with either a highly or weakly metastatic breast cancer cell line using contact (mixture) and non-contact (transwell) co-cultures. mRNA profiles from LECs were subsequently analyzed for genes specifically induced by highly metastatic tumor cells (“metastatic specific”). Among the up-regulated “metastatic specific” genes, we found candidates involved in cell cycle, cell adhesion and motility (BST2, E-selectin, and HMMR), cytokines (CCL7, CXCL6, CXCL1, and CSF2) and factors of the complement system (C1R, C3, and CFB). Among the down-regulated genes, we detected the hyaluronan receptor STAB2, angiogenic factor apelin receptor (APLNR), and the glycosylation enzyme MAN1A1. In an additional prostate cancer co-culture model, we could confirm a “metastatic specific” upregulation of E-selectin and CCL7 in LECs after interaction with the prostate cancer cell lines LNCAP (highly metastatic) and DU145 (weakly metastatic). These data allowed us to identify a set of genes regulated in LECs during in vitro communication with cancer cells, which might subsequently facilitate lymphatic metastasis.

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Effects of syndecan‐4 silencing on the extracellular matrix remodeling in anoikis‐resistant endothelial cells

Onyeisi,

Nader,

Lopes

2024

Cell Biology International

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Anoikis is a process of programmed cell death induced by the loss of cell/matrix interactions. In previous work, we have shown that the acquisition of anoikis resistance upregulates syndecan‐4 (SDC4) expression in endothelial cells. In addition, SDC4 gene silencing by microRNA interference reverses the transformed phenotype of anoikis‐resistant endothelial cells. Due to this role of SDC4 in regulating the behavior of anoikis‐resistant endothelial cells, we have evaluated that the functional consequences of SDC4 silencing in the extracellular matrix (ECM) remodeling in anoikis‐resistant rabbit aortic endothelial cells submitted to SDC4 gene silencing (miR‐Syn4‐Adh‐1‐EC). For this, we evaluated the expression of adhesive proteins, ECM receptors, nonreceptor protein‐tyrosine kinases, and ECM‐degrading enzymes and their inhibitors. Altered cell behavior was monitored by adhesion, migration, and tube formation assays. We found that SDC4 silencing led to a decrease in migration and angiogenic capacity of anoikis‐resistant endothelial cells; this was accompanied by an increase in adhesion to fibronectin. Furthermore, after SDC4 silencing, we observed an increase in the expression of fibronectin, collagen IV, and vitronectin, and a decrease in the expression of integrin α5β1 and αvβ3, besides that, silenced cells show an increase in Src and FAK expression. Quantitative polymerase chain reaction and Western blot analysis demonstrated that SDC4 silencing leads to altered gene and protein expression of MMP2, MMP9, and HSPE. Compared with parental cells, SDC4 silenced cells showed a decrease in nitric oxide production and eNOS expression. In conclusion, these data demonstrate that SDC4 plays an important role in ECM remodeling. In addition, our findings represent an important step toward understanding the mechanism by which SDC4 can reverse the transformed phenotype of anoikis‐resistant endothelial cells.

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Cysteine-linked dimerization of BST-2 confers anoikis resistance to breast cancer cells by negating proapoptotic activities to promote tumor cell survival and growth

Cited by 24 publications

References 38 publications

Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

Mechanisms of Tumor-Lymphatic Interactions in Invasive Breast and Prostate Carcinoma

Effects of syndecan‐4 silencing on the extracellular matrix remodeling in anoikis‐resistant endothelial cells

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