Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Deschesnes, Réna G.; Patenaude, Alexandre; Rousseau, Jean L.C.; Fortin, Jessica S.; Ricard, C.; Côté, Marie‐France; Huot, Jacques; C.‐Gaudreault, René; Petitclerc, Éric

doi:10.1124/jpet.106.110957

Cited by 34 publications

(31 citation statements)

References 37 publications

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“…In this context, it has been reported that in breast cancer cells seeded onto isolated ECM proteins (e.g., fibronectin and type I collagen), β1-integrin is essential to developing resistance to taxolinduced apoptosis (Aoudjit and Vuori, 2001). It is also interesting to note that taxol has been reported to induce focal adhesion disorganization, with the associated taxol-dependent cell death rescued by integrin linked kinase (Deschesnes et al, 2007). Integrin overexpression frequently depresses levels of E-cadherin expression (Thiery and Sleeman, 2006); it has also been reported that loss of E-cadherin causes resistance to taxol (Ferreira et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

et al. 2008

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Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased β1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. β1-integrin-dependent changes in cell resistance to taxol did not correlate with degree of modulation of FAK and Akt, implying additional signaling factors are involved. Based on these results, we propose these matrices potentially have value as in vitro drug screening platforms.

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Section: Discussionmentioning

confidence: 98%

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

et al. 2008

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“…structure (16). Although the direct effect of tubulin deacetylation is not evaluated in these reports, it is possible that deacetylated tubulin affects focal adhesion turnover and regulates anoikis resistance.…”

Section: Discussionmentioning

confidence: 99%

Association of Estrogen Receptor α and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells

et al. 2009

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Estrogen receptor A (ERA) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERA could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERA in breast cancer cells, we generated a construct of membrane-targeted ERA (memER), an expression vector of ERA without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ERA genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERA ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ERA-positive breast cancer cells.

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“…25 Cytoskeletal changes induced by various stimuli have also been shown to regulate integrin activity and the sensitivity to anoikis. 26 In turn chemokine receptors are tightly linked to cytoskeleton remodeling and integrin receptor activation in migrating leukocytes and induce actin polymerization in various cancer cell types. 27,28 Therefore, it is plausible to suggest that chemokine stimulation of metastatic tumor cells, either detached or surrounded by incompatible ECM, leads to actin restructuring, which in combination with other survival signals inhibit anoikis.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

2009

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Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death -anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokineinduced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell -ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors. Cell Death and Differentiation (2009) 16, 664-673; doi:10.1038/cdd.2008; published online 9 January 2009The main cause of cancer-related deaths is the spread of tumor cells to sites distant from the primary locus and the subsequent establishment of secondary lesions. The heterogeneity and complexity of malignant transformation make it difficult to identify common molecular mechanisms governing the metastatic progression of cancer and potentially account for the lack of effective treatments for malignant cancers. Recently, members of the chemokine receptor family of G-protein-coupled receptors (GPCRs) have been assigned a major role in this process (reviewed in Zlotnik 1 ). It is becoming increasingly clear that many members of this family regulate a complex milieu of interactions between tumor cells, stromal cells, tumor infiltrating leukocytes and endothelial cells and that better understanding of the specific actions of chemokines and their receptors in promoting malignancy will significantly contribute to combating cancer. 2 CXCR4 and CCR7 are the major chemokine receptors found on a wide range of tumor cells and high levels of these receptors are associated with higher grade and poor prognosis of breast, lung, colon and other cancers. 3 Blocking the interaction between CXCR4 and its ligand CXCL12, dramatically reduces breast and other cancer metastases in mouse models. 4 Our recent results have also provided a direct correlation between functional activation of CXCR4 and CCR7 and the invasive, metastatic phenotype of breast cancer cells 5 further supporting a highly important role for these molecules in tumor dissemination to distant sites. Initial studies suggested that these surface molecules induce directional migration of ma...

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Microtubule-Destabilizing Agents Induce Focal Adhesion Structure Disorganization and Anoikis in Cancer Cells

Cited by 34 publications

References 37 publications

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

Association of Estrogen Receptor α and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

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