Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epitheliallike morphology; stabilized E-cadherin and b-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased Ecadherin and b-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIBinduced inhibitor of the Wnt/b-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

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“…Cell adhesion and proliferation assays Assays were performed as described previously by Zaric and Ruegg (2005) and Bieler et al (2007).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

et al. 2011

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“…TNF-α induces apoptosis through activation of pro-caspases-8 and -3 (Chua et al 2002), whereas resistance to apoptosis is mainly mediated by the transcription factor NF-kappaB (NF-κB) (Karin and Lin 2002). Alternatively, recent reports indicate that ligation of TNF-α to its receptors leads to cell survival through activation of cell survival pathways that include integrins (Bieler et al 2007). Integrins are cell surface receptors that modulate important cellular processes, some of which involve components of the extracellular matrix (ECM), such as matrix metalloproteinases (MMPs) and their endogenous inhibitors, TIMPs (Karadag and Fisher 2006).…”

Section: Introductionmentioning

confidence: 96%

TIMP-1 interaction with αvβ3 integrin confers resistance to human osteosarcoma cell line MG-63 against TNF-α-induced apoptosis

2010

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Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine affecting diverse cellular responses. TNF-α is cytotoxic in many systems, but it can also act as an anti-apoptotic signal to promote cell survival pathways activated through integrins and extracellular matrix components. This is particularly evident in cancer cells. To unravel the basis of resistance to TNF-α-induced apoptosis, human osteosarcoma MG-63 cell line was used. Our data showed that resistance to apoptosis was accompanied by high levels of TIMP-1 expression in part mediated by NF-κB activation, whereas under apoptotic conditions, in the presence of cycloheximide (CHX), TIMP-1 and αvβ3 integrin protein levels were significantly reduced. Silencing TIMP-1 using siRNA led to increased apoptosis following treatment with TNF-α, whereas exogenously-added recombinant TIMP-1 reduced the extent of apoptosis. Immunoprecipitation and confocal microscopy experiments demonstrated that TIMP-1 interacted with αvβ3 integrins. The biological role of this interaction was revealed by the use of echistatin, an antagonist of αvβ3 integrin. In the presence of echistatin, decreased protection against apoptosis by recombinant TIMP-1 was observed.

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“…In endothelial cells, TNF-mediated modulation of tight-junction proteins is correlated with changes in cell shape (McKenzie and Ridley, 2007). Furthermore, recent reports show that integrin ligation and cellmatrix interaction can modulate TNFα-induced apoptosis independently of NF-κB activation, which demonstrates a crosstalk between integrin and TNF signalling (Bieler et al, 2007;Chen et al, 2007). Depending on the context, tyrosine phosphorylation of components of adherens junctions can lead to stabilization or to internalization of junctions.…”

Section: Other Morphogenetic Effectors Of Tnfmentioning

confidence: 99%

Looking beyond death: a morphogenetic role for the TNF signalling pathway

Mathew

Haubert

Krönke

et al. 2009

Journal of Cell Science

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Tumour necrosis factor α (TNFα) is a pro-inflammatory mediator with the capacity to induce apoptosis. An integral part of its apoptotic and inflammatory programmes is the control of cell shape through modulation of the cytoskeleton, but it is now becoming apparent that this morphogenetic function of TNF signalling is also employed outside inflammatory responses and is shared by the signalling pathways of other members of the TNF-receptor superfamily. Some proteins that are homologous to the components of the TNF signalling pathway, such as the adaptor TNF-receptor-associated factor 4 and the ectodysplasin A receptor (and its ligand and adaptors), have dedicated morphogenetic roles. The mechanism by which TNF signalling affects cell shape is not yet fully understood, but Rhofamily GTPases have a central role. The fact that the components of the TNF signalling pathway are evolutionarily old suggests that an ancestral cassette from unicellular organisms has diversified its functions into partly overlapping morphogenetic, inflammatory and apoptotic roles in multicellular higher organisms.

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Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

Cited by 30 publications

References 36 publications

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

TIMP-1 interaction with αvβ3 integrin confers resistance to human osteosarcoma cell line MG-63 against TNF-α-induced apoptosis

Looking beyond death: a morphogenetic role for the TNF signalling pathway

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