Signaling pathways required for matrix metalloproteinase‐9 induction by betacellulin in head‐and‐neck squamous carcinoma cells

O-charoenrat, Pornchai; Wongkajornsilp, Adisak; Rhys‐Evans, Peter; Eccles, Suzanne A.

doi:10.1002/ijc.20228

Cited by 55 publications

(29 citation statements)

References 39 publications

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“…Increased cellular invasion is often accompanied by increased activity of proteins that degrade the extracellular matrix such as members of the MMP family. In addition, the MAPK and PI3K pathways have been shown to regulate expression of MMP family members (31,37,38). Therefore, we assessed the activity and expression of several members of the MMP family in MCF7/PODXL and PC3/PODXL cells.…”

Section: Resultsmentioning

confidence: 99%

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

et al. 2007

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Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin. [Cancer Res 2007;67(13):6183-91]

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Section: Resultsmentioning

confidence: 99%

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

et al. 2007

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“…The clinical correlation between pERK expression and invasion can be reconciled at the molecular level through activated ERK induction of extracellular matrix-digesting enzymes, facilitating cell migration, and invasion into surrounding tissue. [48][49][50][51] Recently, it has been demonstrated that the invasive capacity of the human renal cell carcinoma cell line Caki-2 is substantially increased on…”

Section: Discussionmentioning

confidence: 99%

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Campbell

Nuttall

Griffiths

et al. 2009

Cancer

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BACKGROUND: Extracellular signal‐regulated kinase (ERK) promotes proliferation, metastasis, and poor survival in cancers of the breast, lung, and liver. Advanced localized renal cell carcinoma (RCC) is extraordinarily treatment resistant and has high recurrence rates despite surgery. Limited data exist regarding the prognostic significance of activated (phosphorylated) ERK in RCC. The authors hypothesized that activated ERK (pERK) promotes disease progression and metastasis in localized RCC and may be of value as a biomarker to predict disease recurrence. METHODS: The expression profile of pERK was examined by immunocytochemistry using a tissue microarray constructed from 174 drug treatment–naive patients who had undergone radical nephrectomy for localized RCC. Levels of tumor‐cell specific pERK were scored and correlated with clinicopathologic parameters of RCC and disease‐free survival. RESULTS: Immunostaining for pERK was present in 36% of all RCCs, with a predominance found in the clear cell histologic subtype. High expression was associated with increased tumor size, increased TNM stage, and vascular invasion. Patients with pERK‐positive tumors had a mean disease‐free survival of 4.19 years, compared with 6.38 years for patients with pERK‐negative tumors (P < .001). Cox regression models revealed pERK to be a significant independent predictor of disease‐free survival, with a hazards score of 2.9 (P < .001), a value similar to tumor grade (hazards ratio, 3.01; P < .001). CONCLUSIONS: Expression of pERK is an independent prognostic factor in RCC that is associated with advanced and aggressive pathologic features of renal tumors and predicts the onset of metastasis in patients with localized disease. Cancer 2009. © 2009 American Cancer Society.

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“…These studies support our immunohistochemical results, which showed decreased protein expression of MMP-9 after treatment with the EGFR inhibitor AEE788. Furthermore, other research has shown that blocking of phosphatidylinositol 3-kinase by selective inhibitors effectively inhibited betacellulin-enhanced MMP-9 expression in head and neck squamous cell carcinoma cells, indicating that phosphatidylinositol 3-kinase/Akt is required in this process (27,28). MMP-9 has a nuclear factor nB (NF-nB) binding site in its promoter region and, therefore, expression of MMP-9 is regulated by NF-nB transcriptional activity (28).…”

Section: Discussionmentioning

confidence: 99%

Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model

Younes¹,

Park²,

Yazici³

et al. 2006

Molecular Cancer Therapeutics

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We hypothesized that epidermal growth factor (EGF) receptor (EGFR) activation and vascular endothelial growth factor (VEGF) -induced angiogenic signals are important for the progression and metastasis of human salivary adenoid cystic carcinoma (ACC). To test this hypothesis, we evaluated the therapeutic effect of AEE788, a dual inhibitor of EGF and VEGF receptor (VEGFR) tyrosine kinases, on human salivary ACC. In clinical specimens of salivary ACC, EGF and VEGF signaling proteins were expressed at markedly higher levels than in adjacent normal glandular tissues. We examined the effects of AEE788 on salivary ACC cell growth and apoptosis and on the phosphorylation of EGFR and VEGFR-2 in salivary ACC cells. Treatment of salivary ACC cells with AEE788, alone or in combination with chemotherapy, led to growth inhibition, induction of apoptosis, and dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation. To determine the in vivo antitumor effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 alone, paclitaxel alone, cisplatin alone, a combination of AEE788 plus paclitaxel, a combination of AEE788 plus cisplatin, or a placebo. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. To study the mechanism of interaction between AEE788 and chemotherapy, AEE788 was found to potentiate growth inhibition and apoptosis of ACC tumor cells mediated by chemotherapy. Tumors of mice treated with AEE788 and AEE788 plus chemotherapy exhibited down-regulation of activated EGFR and VEGFR-2, increased tumor and endothelial cell apoptosis, and decreased microvessel density, which correlated with a decrease in the level of matrix metalloproteinase-9 and matrix metalloproteinase-2 expression and a decrease in the incidence of vascular metastasis. These data show that EGFR and VEGFR can be molecular targets for therapy of salivary ACC.

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Signaling pathways required for matrix metalloproteinase‐9 induction by betacellulin in head‐and‐neck squamous carcinoma cells

Cited by 55 publications

References 39 publications

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model

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