Actopaxin (α-Parvin) Phosphorylation Is Required for Matrix Degradation and Cancer Cell Invasion

Pignatelli, Jeanine; LaLonde, Sara E.; LaLonde, David P.; Clarke, Dominic M.; Turner, Christopher E.

doi:10.1074/jbc.m112.385229

Cited by 34 publications

(21 citation statements)

References 52 publications

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“…In accordance, overexpression of α-parvin in human hepatocellular carcinomas (HCC) correlates with metastasis and decreased survival (13). In further support, α-parvin has been shown to induce HCC cell invasion and metastasis and phosphorylation of α-parvin has been demonstrated to be required for matrix degradation and cell invasion (14,26). However, conflicting results have been reported for βparvin.…”

Section: Discussionmentioning

confidence: 87%

Focal Adhesion Proteins α- and β-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression

Bravou

Antonacopoulou

Papanikolaou

et al. 2015

Cancer Investigation

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This study aims to address the role of focal adhesion proteins α- and β-parvin in human colorectal carcinoma (CRC). Expression of α- and β-parvin was examined by immunohistochemistry and real-time RT-PCR in a series of human CRC. Parvins were overexpressed in CRC and their expression correlated significantly with tumor invasion, lymph node metastasis, and disease stage. A significant positive correlation of parvins protein expression with overexpression of integrin-linked kinase, p-AKT, and nuclear β-catenin, as well as with downregulation of E-cadherin was also observed. In conclusion, overexpression of α- and β-parvin seems to be implicated in human colorectal cancer progression.

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Section: Discussionmentioning

confidence: 87%

Focal Adhesion Proteins α- and β-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression

Bravou

Antonacopoulou

Papanikolaou

et al. 2015

Cancer Investigation

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“…This study demonstrates for the first time the clinical significance of actopaxin in HCC, and that actopaxin was involved in the regulation of cell invasion, migration, and metastasis of HCC. While this article was in preparation, Pignatelli et al showed that actopaxin phosphorylation is required for matrix degradation and cancer cell invasion in their osteosarcoma and breast cancer cell line models, via regulation of RhoGTPase signaling. Their results, in combination with our findings in this study, revealed the significant role of actopaxin in cancer cell metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Actopaxin, a focal adhesion protein, associates with many other focal adhesion molecules to regulate cellular events including cell adhesion and spreading as well as cell migration . More important, its phosphorylation has been recently shown to induce matrix degradation, cell migration, and invasion in breast cancer cell line models . Yet the clinical significance of actopaxin has not been demonstrated so far.…”

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confidence: 99%

Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion

Poon

Yau

et al. 2013

Hepatology

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Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelialmesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, b-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. Conclusion: This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs. (HEPATOLOGY 2013;58:667-679) H epatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. 1Most HCC patients die from locally advanced or metastatic disease in a relatively short period of time, and the mechanisms responsible for HCC progression and metastasis remain a major challenge to researchers in this field. It is believed that the elucidation of molecular mechanisms involved in HCC progression and metastasis is important for development of HCC therapeutic agents.Tumor invasion and metastasis are complex processes requiring the ability of tumor cells to interact with the extracellular matrix. Major cell surface receptors that mediate these interactions are integrins.2 Several studies have demonstrated the important roles of b1-integrin in the growth, invasiveness, and metastatic potential of HCC, 3-5 as well as in protecting cancer cells against chemotherapeutic-drug-induced apoptosis.6 Focal adhesion proteins serve as a structural and signaling nexus connecting integrins and the dynamic Abbreviations: 97L-LUC cells, luciferase incorporated...

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“…For zymographic studies, 5 × 10 4 cells were plated plated on 18 mm collagen-coated glass coverslips and incubated for 24 hrs. The media was collected and centrifuged at 2000 rpm for 30 min to remove dead cells and any other debris, and supernatants were lyophilized for zymographic experments, as described elsewhere [25]. In case of drug studies, cells were allowed to adhere to the substate for 4 hours, after which fresh media containing drug at desired concentration was added.…”

Section: Gelatin Zymographymentioning

confidence: 99%

Extracellular Matrix Density Regulates Extracellular Proteolysis via Modulation of Cellular Contractility

Das¹,

Kapoor²,

Mehta³

et al. 2013

J Carcinogene Mutagene

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The Extracellular Matrix (ECM) undergoes changes in composition and organization during tumor progression. In breast cancer, increased deposition and cross linking-induced alignment of collagen I create a stiffer microenvironment that directly contributes to cancer invasion. While ECM stiffness-induced invasion has been documented, it remains unclear if ECM density also contributes to invasion independent of ECM stiffness. In this paper, using collagen I-coated glass coverslips of varying density, we sought to study the influence of ECM density on the invasiveness of human MDA-MB-231 breast cancer cells. We first showed that cell spreading and contractility increases with ECM density. Concomitant with increase in cell contractility, matrix degradation was seen to increase with ECM density and was associated with higher invadopodia activity. The density-dependent increase in degradation was associated with higher activity of MMP-2, MMP-9 and MT1-MMP. Treatment with either the MMP inhibitor GM6001 or the myosin II inhibitor blebbistatin, were found to inhibit cell contractility and suppress matrix degradation. Contractility was found to modulate the activity of MMP-2 and MMP-9, and the localization of MT1-MMP at invadopodia. Taken together, our results indicate that ECM density regulates ECM degradation through modulation of cell contractility.

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Actopaxin (α-Parvin) Phosphorylation Is Required for Matrix Degradation and Cancer Cell Invasion

Cited by 34 publications

References 52 publications

Focal Adhesion Proteins α- and β-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression

Focal Adhesion Proteins α- and β-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression

Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion

Extracellular Matrix Density Regulates Extracellular Proteolysis via Modulation of Cellular Contractility

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