Role of Focal Adhesion Kinase and Phosphatidylinositol 3′-Kinase in Integrin Fibronectin Receptor-Mediated, Matrix Metalloproteinase-1–Dependent Invasion by Metastatic Prostate Cancer Cells

Zeng, Zhi; Jia, Yan; Hahn, Nathan J.; Markwart, Sonja; Rockwood, Korrene F.; Livant, Donna L.

doi:10.1158/0008-5472.can-05-4400

Cited by 89 publications

(94 citation statements)

References 53 publications

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“…Our current findings indicate that the ECM glycoprotein, fibronectin, specifically promotes A549 lung cancer cell migration and invasion. Consistent with previous reports that FAK has a critical role in promoting cell migration and invasion (Mukhopadhyay et al, 2005;Zeng et al, 2006), we found an increased activation of FAK in A549 cells grown in fibronectin-coated plates. Focal adhesion kinase activation was determined by increased phosphorylation of FAK at its Tyr397, Tyr861, and Tyr925 residues.…”

Section: Discussionsupporting

confidence: 93%

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Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

et al. 2009

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BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in a variety of cancers, such as breast, colon, prostate, ovary, and lung cancers. However, the mechanism by which extracellular matrix fibronectin stimulates lung cancer cell migration and invasion through FAK remains to be investigated. METHODS: The signalling pathways in fibronectin-mediated lung cancer cell migration and invasion were examined using western blotting. The metastasis function was detected by wound healing, migration and invasion assays. Further, RNA interference and kinase inhibitors were also used to study the downstream signals. RESULTS: In this study, we examined the FAK signalling pathways in relation to calpain-2 and RhoA in fibronectin-mediated lung cancer cell migration and invasion. We found that A549 lung epithelial cells stimulated by fibronectin showed increased phosphorylation of FAK and its downstream targets, Src, ERK1/2, phosphatidylinositol 3 0 -kinase (PI3K), and Akt. Consistent with this observation, depletion of FAK by siRNA resulted in the inhibition of Src, ERK1/2, PI3K, and Akt activity. In addition, the Src inhibitor, PP2, blocked the phosphorylation of FAK, ERK1/2, PI3K, and Akt. Conversely, inhibition of MEK1/2 using PD98059 reduced the expression of matrix metalloproteinase-9 (MMP9) and calpain-2. The PI3K inhibitor, LY294002, further blocked the expression of MMP9 and RhoA. Inhibition of both MEK1/2 and PI3K caused reduced cell migration and invasion. CONCLUSIONS: Our data suggest that fibronectin-mediated activation of FAK that leads to lung cancer metastasis could occur through ERK or PI3K/Akt regulation of MMP9/calpain-2 or MMP9/RhoA activity, respectively.

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Section: Discussionsupporting

confidence: 93%

“…There have been suggestions that activation of PI3K regulates the migration and invasion of various cancer cells (Reiske et al, 1999;Zeng et al, 2006). Despite these findings, the specific role of PI3K in controlling lung cancer cell migration and invasion, particularly in relation to FAK signalling, has been elusive.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

et al. 2009

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“…This FAK signalling pathway also seems to operate in noncancerous cells (Segarra et al, 2005). There have been reports linking other extracellular proteases, such as MMP-9 (Mon et al, 2006a), MMP-1 (Zeng et al, 2006) and uPA with FAK signalling in other tumour cell types, but until now MMP-2 has not been reported to be involved. Therefore, distinct downstream signalling pathways are active in a tumour cell typedependent manner.…”

Section: Discussionmentioning

confidence: 97%

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

et al. 2008

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Focal adhesion kinase (FAK) is considered intimately involved in cancer progression. Our previous research has demonstrated that overexpression of FAK is an early and frequent event in squamous cell carcinomas of the supraglottic larynx, and it is associated with the presence of metastases in cervical lymph nodes. The purpose of this study was to examine the functional role of FAK in the progression of head and neck squamous cell carcinomas (HNSCC). To this end, expression of FAK-related nonkinase (FRNK) or small interfering RNA (siRNA) against FAK was used to disrupt the FAK-induced signal transduction pathways in the HNSCC-derived SCC40 and SCC38 cell lines. Similar phenotypic effects were observed with the two methodological approaches in both cell lines. Decreased cell attachment, motility and invasion were induced by FRNK and FAK siRNA, whereas cell proliferation was not impaired. In addition, increased cell invasion was observed upon FAK overexpression in SCC cells. FRNK expression resulted in a downregulation of MMP-2 and MMP-9 expression. Interestingly, MMP-2 overexpression in FRNK-expressing cells rescued FRNK inhibition of cell invasion. This is the first demonstration of a direct rescue of impaired cell invasion by the re-expression of MMP-2 in a tumour cell type with decreased expression of functional FAK. Collectively, these data reported here support the conclusion that FAK enhances invasion of HNSCC by promoting both increased cell motility and MMP-2 production, thus providing new insights into possible therapeutic intervention strategies. Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, comprising B50% of all malignancies in some developing nations. HNSCC is associated with severe disease-and treatment-related morbidity and has a 5-year survival rate of B50%. This survival rate has remained largely unchanged in the past three decades (Sankaranarayanan et al, 1998;Gonzalez-Botas and Vazquez Barro, 2006). A major determinant of the lethal progression of HNSCC is the spreading of the malignant cells to regional lymph nodes which represents a major prognostic indicator (Forastiere et al, 2001). Thus, attempts to identify the genes involved in metastasis are pivotal for the early prediction of HNSCC behaviour and development of novel molecular therapies. However, the identities of molecular alterations that endow cancer cells with these metastatic functions are largely unknown.The process of metastasis consists of sequential and selective steps including proliferation, motility, invasion, loss of cell -cell and cell -matrix adhesion, and remodelling of the extracellular matrix. A key factor involved in the control of cellextracellular matrix interactions is focal adhesion kinase (FAK), an intracellular tyrosine kinase protein that is localised to cellular focal contact sites (Schaller et al, 1992). Initially, phosphorylation of FAK occurs on its major autophosphorylation site, Tyr 397 . Phosphorylation of this tyrosine initiates a cascade of signal transdu...

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“…There is also evidence that PKCd can enhance cell motility, possibly by affecting the expression and activity of b1 integrins and focal adhesion kinase (Chen et al 2007, Brenner et al 2008. Furthermore, PKCd has been shown to act to promote invasiveness in prostate and breast cancer cells (Kiley et al 1999, Kharait et al 2006, Villar et al 2007, and rottlerin has been shown to completely prevent invasion induced by the integrin-activating peptide PHSRN in DU-125 prostate cancer cells (Zeng et al 2006). We have shown that both FSH and LH induce migration in ovarian cancer cells that is dependent upon ERK1/2 and PKCd signalling.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Mertens‐Walker¹,

Bolitho²,

Baxter³

et al. 2010

Endocrine-Related Cancer

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The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra-and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCd inhibitor rottlerin, and downregulation of PKCd was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCd in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCd siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium-and PKCd-dependent manner.

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Role of Focal Adhesion Kinase and Phosphatidylinositol 3′-Kinase in Integrin Fibronectin Receptor-Mediated, Matrix Metalloproteinase-1–Dependent Invasion by Metastatic Prostate Cancer Cells

Cited by 89 publications

References 53 publications

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

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