Molecular Mediators of α&lt;sub&gt;v&lt;/sub&gt;β&lt;sub&gt;3&lt;/sub&gt;-Induced Endothelial Cell Survival

Rice, Julie; Courter, Donald; Giachelli, Cecilia M.; Scatena, Marta

doi:10.1159/000094884

Cited by 29 publications

(16 citation statements)

References 153 publications

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“…Earlier reports suggested that OPN regulates avb 3 integrin mediated NF-kB activation in various cancer and endothelial cells (20)(21)(22)(23)(24)47). The integration of signaling by c-jun Nterminal kinase (JNK) and p38 MAPK plays crucial role in the development of many cancers (48).…”

Section: Discussionmentioning

confidence: 99%

p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

Kumar

Behera²,

Lohite³

et al. 2010

Cancer Research

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Abstractp38 kinases activated by growth factors, hormones, and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology. Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer, although the mechanistic basis for this association is poorly understood. In this study, we report that p38 activation in cervical cancer cells is driven by osteopontin (OPN), an extracellular matrix-associated cytokine that drives invasive progression. OPN regulates CD44-mediated p38 phosphorylation that induces NF-kB activation and NF-kB-dependent expression of furin, an extracellular protease implicated in human papilloma virus (HPV) processing that enhances cervical cancer cell motility. OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells. OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6, p38a/b or NF-kB signaling. In a mouse xenograft model of human cervical cancer, tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA (shRNA)-mediated OPN silencing. Furin overexpression similarly augmented tumor growth in the model, whereas blocking MKK3/6, p38, or furin reduced OPN-induced cervical tumor growth. Analysis of clinical specimens revealed that enhanced expression of OPN, phosphorylated NF-kB, p65, and furin correlated with cervical cancer progression, further strengthening the in vitro and in vivo results. In summary, our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer.

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Section: Discussionmentioning

confidence: 99%

p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

Kumar

Behera²,

Lohite³

et al. 2010

Cancer Research

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“…Anti-apoptotic effects of OPN have also been reported for endothelial cells and are mediated through the activation of NF-kB [47,48].…”

Section: Osteopontinmentioning

confidence: 96%

Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis

Chiodoni

Colombo

Sangaletti

2010

Cancer Metastasis Rev

203

177

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The family of matricellular proteins comprises molecules with disparate biology. The main characteristic of matricellular proteins is to be expressed during tissue renewal and repair in order to "normalize" the tissue. Tumors are wound that do not heal, and tumor growth and metastasis can be viewed as a consequence of aberrant homeostasis, during which matricellular proteins are often upregulated. In the tumor microenvironment, they can be produced by both tumor cells and surrounding stromal cells, such as fibroblasts and macrophages. In this context, matricellular proteins can exert several functions that actively contribute to tumor progression. They may (a) regulate cellular adhesion and migration and extracellular matrix deposition, (b) control tumor infiltration by macrophages or other leukocytes, (c) affect tumor angiogenesis, (d) regulate TGFbeta and other growth factor receptor signals, (e) directly stimulate integrin receptors to transduce pro-survival or pro-migratory signals, and (f) regulate the wnt/beta-catenin pathways. Most of these functions contribute to settle a chronic low inflammatory state, whose involvement in tissue transformation and tumor progression is now established.

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“…OPN signaling through the αvβ3 integrin can modulate (via activation of ras and src) the phosphorylation of kinases (NIK, IKKβ) involved in NFκB activation (Rice et al, 2006, Scatena et al, 1998; this results in the degradation of IκB, an inhibitor of NFκB (Vejda et al, 2005). NFκB regulates expression of many inflammatory cytokines.…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Osteopontin: Role in immune regulation and stress responses

Wang¹,

Denhardt²

2008

Cytokine & Growth Factor Reviews

609

558

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Molecular Mediators of α<sub>v</sub>β<sub>3</sub>-Induced Endothelial Cell Survival

Cited by 29 publications

References 153 publications

p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression

Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis

Osteopontin: Role in immune regulation and stress responses

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