SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Chang, Wenteh; Wei, Ke; Jacobs, Susan S.; Upadhyay, Daya; Weill, David; Rosen, Glenn D.

doi:10.1074/jbc.m109.025684

Cited by 95 publications

(116 citation statements)

References 43 publications

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“…Previous studies have shown that cycloheximide alone is insufficient to induce fibroblast apoptosis (11,35), a finding that was confirmed in a subset of experiments for each of the different fibroblast populations studied. Together, these findings are consistent with prior studies showing that normal fibroblasts are relatively resistant to Fas-mediated apoptosis, that IPF lung fibroblasts have increased resistance to Fas-mediated apoptosis compared with normal lung fibroblasts, and that cycloheximide "sensitizes" normal and IPF fibroblasts to undergo robust apoptosis upon Fas activation (8,10,12,(33)(34)(35)(37)(38)(39). Additionally, these findings demonstrate that IMR-90 and CCL-210 fibroblasts exhibit Fas-induced apoptotic responses that are indistinguishable from primary normal lung fibroblasts isolated from lung explants.…”

Section: Ipf Lung Fibroblasts Have Decreased Susceptibility To Fas-mesupporting

confidence: 90%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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Section: Ipf Lung Fibroblasts Have Decreased Susceptibility To Fas-mesupporting

confidence: 90%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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“…This process, although unable to replace tissue or organ function (eg, myocardial scarring after infarction), is in most cases controlled, and its regulation is strictly dependent on the resolution of the underlying inflammatory spur. SPARC is a matricellular glycoprotein involved in fibrosis 3,4,7,34 through unknown mechanisms, in addition to its role in collagen and ECM deposition. 35,36 An impaired ECM deposition or the absence of SPARC is associated with increased inflammatory infiltration and immune cell migration.…”

Section: Discussionmentioning

confidence: 99%

SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage

Sangaletti

Tripodo

Cappetti

et al. 2011

The American Journal of Pathology

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“…SPARC was originally identified as a stress response gene (Sage et al, 1986), and subsequently described as a c-Jun-responsive target gene that can be repressed or induced depending on cell type (Mettouchi et al, 1994;Briggs et al, 2002). Consistent with a role of SPARC in cellular stress, recent studies showed that SPARC protects lens epithelial cells from stress-induced apoptosis and suppresses apoptosis in pulmonary fibroblasts (Weaver et al, 2008;Chang et al, 2010).…”

Section: Discussionmentioning

confidence: 92%

“…The intracellular signaling pathways downstream from SPARC are beginning to be identified. They include major mediators of integrin signaling such as integrin-linked kinase (ILK) and focal adhesion kinase (FAK) (Barker et al, 2005;Shi et al, 2007;Weaver et al, 2008), as well as b-catenin and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathways (Shi et al, 2004;Nie and Sage, 2009;Chang et al, 2010). In cancer, SPARC may function as either a tumor suppressor or a pro-invasive factor depending on the tumor type and local extracellular milieu.…”

Section: Introductionmentioning

confidence: 99%

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

et al. 2011

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Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.

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SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Cited by 95 publications

References 43 publications

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

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