Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells

Slack, Jill K.; Adams, Reid B.; Rovin, Joshua D.; Bissonette, Eric A.; Stoker, Catherine E; Parsons, J. Thomas

doi:10.1038/sj.onc.1204208

Cited by 194 publications

(159 citation statements)

References 56 publications

(78 reference statements)

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“…These observations support the results of our study. Slack et al demonstrated that an increase in FAK expression, coupled with tyrosine phosphorylation of FAK on tyrosine 861, may contribute to the increased cell motility of highly tumorigenic prostate cancer cells (Slack et al, 2001). Overexpression of FAK may alter the motility of ESCC cells, and as a result of this high motility, FAK protein might be overexpressed in those patients with more invasive and metastatic ESCC.…”

Section: Discussionmentioning

confidence: 99%

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

et al. 2003

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Focal adhesion kinase (p125 FAK ; 'FAK') is a tyrosine kinase that is localised to cellular focal adhesions and is associated with a number of other proteins, such as integrin adhesion receptors. We performed an immunohistochemical analysis of FAK protein expression to determine the relationship between FAK overexpression and clinicopathological factors in oesophageal squamous cell carcinoma (ESCC). We examined tissue specimens that had been removed from 91 patients with thoracic oesophageal cancer who had undergone surgery between 1983 and 2001. Immunohistochemical staining was performed by the standard streptavidin -biotin method. Seven human ESCC cell lines -TE-1, TE-2, TE-8, TE-13, TE-15, TT, and TTn -and one immortalized human keratinocyte cell line -HaCaT -were used in Western blot analysis. Immunostaining of FAK was seen in the cytoplasm of cancer cells, particularly in cells located in the invasive fronts of cancer nests. FAK overexpression was detected in 54 of the 91 patients (59.3%). Significant correlations were observed between FAK overexpression and cell differentiation (P ¼ 0.0057), depth of tumour invasion (P ¼ 0.0023), presence of regional lymph node metastasis (P ¼ 0.0097), number of lymph node metastases (P ¼ 0.0026), and disease stage (P ¼ 0.012). The survival rates of patients with FAK-overexpressing cancer were significantly lower than those of patients without FAK-overexpression cancer (P ¼ 0.006). The 5-year survival rate of patients without FAK overexpression was 69%, whereas that of patients with FAK overexpression was 38%. On Western blot analysis, FAK was expressed at a high level in TE-1, TE-8, TE-15, and TT cells, at a moderate level in TE-2 and TTn cells, and at a low level in TE13 and HaCaT cells. FAK phosphorylation at tyrosine 397 was demonstrated in proportion to the intensity of FAK in all cell lines except TE15 and HaCaT. In conclusion, FAK overexpression of ESCC was related to cell differentiation, tumour invasiveness, and lymph node metastasis. Consequently, patients with ESCC who had FAK overexpression had a poor prognosis.

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Section: Discussionmentioning

confidence: 99%

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

et al. 2003

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“…Although activation of Src has been positively correlated with both cell proliferation and invasiveness of several prostate cancer cell lines, 17,18,21 no data are currently available on the activation of Src in primary prostate tumors. Herein we have investigated activation of Src by assaying the level of tyrosine phosphorylation of the kinase, which is directly correlated to its activity status.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 Furthermore, Sam68 is highly expressed in prostate epithelial cells and the involvement of this protein in RNA metabolism during normal growth and neoplastic transformation of prostatic cells has recently been hypothesized. 19 Herein we undertook an analysis of prostate cancer cell lines and primary prostatic tumors for the presence of human tr-Kit.…”

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confidence: 99%

Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer

Paronetto

Farini

Sammarco

et al. 2004

The American Journal of Pathology

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The c-Kit receptor belongs to type III tyrosine kinase receptor, which consists of an extracellular ligand binding domain and an intracellular kinase domain. In the kinase domain, the ATP binding site is separated from the phosphotransferase site by an interkinase sequence required for interaction with signal transduction proteins involved in the c-Kit pathway. 1 The c-Kit receptor is expressed in a wide variety of normal and neoplastic tissues. A positive correlation between misregulation of the c-kit gene and malignant transformation of cells has been reported. 2,3 For instance, substitution mutations in exon 11 of the gene, changing amino acids of the juxtamembrane region of the receptor, are associated with gastrointestinal stromal tumors, whereas mutations in exon 17 that substitute Asp816, just downstream of the tyrosine kinase signature, are associated with myeloid leukemias and testicular seminomas. 2,3 These mutations induce ligand-independent dimerization or autophosphorylation of the receptor and they cause constitutive activation of downstream signaling pathways. Moreover, overexpression of c-Kit and its ligand SCF occurs in several tumors and they probably stimulate proliferation in an autocrine or paracrine manner. 2 Recently, c-kit expression in various tumors has been revisited because this receptor is a target of the anti-cancer activity of a well described tyrosine kinase inhibitor: imatinib (STI1571). 2,4 Beside mutations affecting the activity of the full-length c-Kit, expression of an alternative transcript of human c-kit has been described in several transformed cell lines. The

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“…Whereas high levels of FRNK can promote cell apoptosis (Xu et al, 2000;Golubovskaya et al, 2002), FRNK expression can also reduce tumor growth by promoting tumor dormancy and by inhibiting cell proliferation (Aguirre Ghiso, 2002;van Nimwegen et al, 2005). Low levels of FRNK expression have revealed the importance of FAK activity in promoting tumor cell migration (Slack et al, 2001) and in generating an invasive cell phenotype (Hauck et al, 2001(Hauck et al, , 2002bHsia et al, 2003;.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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Expression of focal adhesion kinase (FAK) is elevated in malignant breast cancer, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. Here, we have inhibited FAK activity or expression in murine 4T1 breast carcinoma cells via dominantnegative focal adhesion kinase-related non-kinase (FRNK) or anti-FAK short hairpin RNA (shRNA) expression, respectively. Neither FRNK nor FAK shRNA (B80% reduced FAK levels) affected 4T1 proliferation in culture, whereas reduced FAK activity or expression blocked 4T1 cell invasion through Matrigel and resulted in 2-3-fold lower urokinase plasminogen activator (uPA) expression. Control 4T1 cells implanted into mammary fat pads of BALB/c mice exhibited spontaneous metastasis to the lungs, to the peritoneal cavity, and resulted in 90% lethality within 21 days. Whereas FAK shRNAexpressing 4T1 cells formed tumors in mice with low levels of apoptosis, when mammary-injected, these cells did not exhibit lung metastasis after 21 days and caused only 40% lethality up to 60 days. Transient re-expression of wildtype but not kinase-dead FAK in 4T1 FAK shRNA cells promoted uPA production and mammary to lung metastasis within 7 days. In fact, stable human uPA overexpression in 4T1 FAK shRNA cells promoted Matrigel invasion and lung metastasis equal to 4T1 controls. Conversely, treatment with plasminogen activator inhibitor-1 or neutralizing antibody to uPA blocked Matrigel invasion of 4T1 control cells. These studies provide the first direct proof that FAK catalytic activity can facilitate metastatic breast cancer progression by regulating uPA expression.

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Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells

Cited by 194 publications

References 56 publications

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

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