Induction of Lung Fibroblast Apoptosis by Soluble Fibronectin Peptides

Hadden, Hélène; Henke, Craig A.

doi:10.1164/ajrccm.162.4.2001015

Cited by 63 publications

(51 citation statements)

References 25 publications

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“…Fibronectin binds to alpha5 beta1 integrin through the well-known Arg-Gly-Asp (RGD) binding motif within the Type III domain. The significance of this interaction between fibronectin and integrin in adhesion-mediated survival has been characterized with synthetic agents that competitively bind to the RGD-binding site and enhance apoptosis (Buckley et al, 1999;Hadden and Henke, 2000). Our findings of expression of fibronectin in both anaplastic astrocytomas and glioblastomas in frozen tumor specimens suggest a potential mechanism in promoting resistance to chemotherapy.…”

Section: Discussionmentioning

confidence: 68%

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

et al. 2006

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Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N 0 -bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

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Section: Discussionmentioning

confidence: 68%

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

et al. 2006

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“…Detachment from the matrix precipitates anoikis (7,8). Fibroblasts are more resistant than epithelial cells to the process of anoikis (43). However, if deprived of matrix contact for prolonged time periods, fibroblasts also undergo anoikis (43,44).…”

Section: Discussionmentioning

confidence: 99%

“…Fibroblasts are more resistant than epithelial cells to the process of anoikis (43). However, if deprived of matrix contact for prolonged time periods, fibroblasts also undergo anoikis (43,44). Because, in our system, fibroblasts were embedded in three-dimensional collagen gels, loss of attachment to the ECM is unlikely to be the mechanism by which fibroblasts undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

β1 Integrin Regulates Fibroblast Viability during Collagen Matrix Contraction through a Phosphatidylinositol 3-Kinase/Akt/Protein Kinase B Signaling Pathway

Tian

Lessan

Kahm

et al. 2002

Journal of Biological Chemistry

150

145

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Integrins regulate cell viability through their interaction with the extracellular matrix. Integrins can sense mechanical forces arising from the matrix and convert these stimuli to chemical signals capable of modulating intracellular signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is a major regulator of cell survival. It is not known, however, whether integrins, acting as mechanoreceptors, regulate cell survival via the PI3K/Akt pathway. Here, we show that in response to a matrix-derived mechanical stimulus, ␤ 1 integrin regulated cell viability by regulating Akt activity in a PI3K-dependent fashion. To accomplish this, we employed fibroblasts cultured in collagen gels. During contraction of collagen matrices, fibroblasts underwent apoptosis. We demonstrate that ligation of ␤ 1 integrin with anti-␤ 1 integrin antibodies protected fibroblasts from apoptosis. The nature of the survival signal activated by ␤ 1 integrin engagement with antibody was mediated by PI3K acting through Akt/protein kinase B. We show that Akt phosphorylation decreased during collagen contraction and that this decrease correlated precisely with the onset of fibroblast apoptosis. Fibroblasts transfected with constitutively active PI3K displayed increased Akt phosphorylation and were protected from anoikis and collagen gel contraction-induced apoptosis. Our data identify a novel role for ␤ 1 integrin in regulating fibroblast viability through a PI3K/Akt/protein kinase B signaling pathway in response to a matrix-derived mechanical stimulus.

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“…The exogenous addition of soluble peptides containing the arginine-glycine-aspartate (RGD) amino acid sequence has been shown to disrupt cell adhesion signalling [26,27]. We first determined if introduction of an RGD-containing peptide modulates FAK autophosphorylation in IMR-90 fibroblasts.…”

Section: Induction Of Akt Activation By Tgf-β1 Is Independent Of Fak mentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

224

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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Induction of Lung Fibroblast Apoptosis by Soluble Fibronectin Peptides

Cited by 63 publications

References 25 publications

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy

β1 Integrin Regulates Fibroblast Viability during Collagen Matrix Contraction through a Phosphatidylinositol 3-Kinase/Akt/Protein Kinase B Signaling Pathway

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

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