Transforming Growth Factor-α Prevents Detachment-induced Inhibition of c-Src Kinase Activity, Bcl-XLDown-regulation, and Apoptosis of Intestinal Epithelial Cells

Rosen, Kirill V.; Loza-Coll, Mariano; Li, Alwin; Filmus, Jorge

doi:10.1074/jbc.m106424200

Cited by 140 publications

(80 citation statements)

References 57 publications

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“…This view is consistent with our observation that activated TGF-b does not prevent, but just attenuates the apoptotic death of HUVECs (Figures 7 and 8). Similar protective effects against at least anoikis of intestinal epithelial cells have recently been reported for TGF-a, 41 suggesting a common role for different TGFs in the modulation of apoptotic cell death. Interestingly, exogenous TGF-a exerted its protective effect by partial reversion of detachment-induced inhibition of c-Src kinase activity and Bcl-X(L) expression.…”

Section: Discussionsupporting

confidence: 69%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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Transforming growth factors b (TGF-bs) are multifunctional cytokines that modulate cell growth, differentiation and apoptosis. Numerous effects initiated by TGF-bs in vitro have been described, but the role of TGF-b targeting and activation under physiological conditions has gained very little attention and understanding. We report here that apoptosis of human umbilical vein endothelial cells (HUVECs) is accompanied by release of truncated large latent TGF-b complexes from the pericellular matrix followed by activation of TGF-b. The activation of TGF-b during apoptosis was accompanied by enhanced secretion of b1-LAP protein, and apoptotic HUVECs acquired the capacity to induce the release of latent TGF-bbinding proteins (LTBPs) from extracellular matrices. Activated TGF-b, in turn, attenuated apoptotic death of HUVECs. Current results indicate that the activation of TGF-b accompanies the apoptosis of HUVECs, and may play a protective feedback role against apoptotic cell death. The results suggest a role for TGF-b as a putative extracellular modulator of apoptosis.

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Section: Discussionsupporting

confidence: 69%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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“…Epidermal growth factor receptor signalling promotes angiogenesis, cell proliferation, tumour invasion and inhibits tumour suppressor gene activity and apoptotic signalling (Westermark et al, 1982;Abdollahi et al, 1999;Rosen et al, 2001;Gildea et al, 2002;Hirata et al, 2002;Di Gennaro et al, 2003). Recently, the clinical relevance of the EGFR has been heightened in light of the development of the EGFR tyrosine kinase inhibitors, Getifinib and Erlotinib and EGFR monoclonal antibodies Cetuximab that have been demonstrated to have antitumour activity in solid tumours including non-small cell lung cancer (NSCLC) Herbst et al, 2004a, b;Lynch et al, 2004b).…”

mentioning

confidence: 99%

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer

2004

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The epidermal growth factor receptor (EGFR) is commonly expressed in non-small-cell lung cancer (NSCLC) and promotes a host of mechanisms involved in tumorigenesis. However, EGFR expression does not reliably predict prognosis or response to EGFR-targeted therapies. The data from two previous studies of a series of 181 consecutive surgically resected stage I -IIIA NSCLC patients who had survived in excess of 60 days were explored. Of these patients, tissue was available for evaluation of EGFR in 179 patients, carbonic anhydrase (CA) IX in 177 patients and matrix metalloproteinase-9 (MMP-9) in 169 patients. We have previously reported an association between EGFR expression and MMP-9 expression. We have also reported that MMP-9 (P ¼ 0.001) and perinuclear (p)CA IX (P ¼ 0.03) but not EGFR expression were associated with a poor prognosis. Perinuclear CA IX expression was also associated with EGFR expression (Po0.001). Multivariate analysis demonstrated that coexpression of MMP-9 with EGFR conferred a worse prognosis than the expression of MMP-9 alone (Po0.001) and coexpression of EGFR and pCA IX conferred a worse prognosis than pCA IX alone (P ¼ 0.05). A model was then developed where the study population was divided into three groups: group 1 had expression of EGFR without coexpression of MMP-9 or pCA IX (number ¼ 21); group 2 had no expression of EGFR (number ¼ 75); and group 3 had coexpression of EGFR with pCA IX or MMP-9 or both (number ¼ 70). Group 3 had a worse prognosis than either groups 1 or 2 (P ¼ 0.0003 and 0.027, respectively) and group 1 had a better prognosis than group 2 (P ¼ 0.036). These data identify two cohorts of EGFR-positive patients with diametrically opposite prognoses. The group expressing either EGFR and or both MMP-9 and pCA IX may identify a group of patients with activated EGFR, which is of clinical relevance with the advent of EGFR-targeted therapies.

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“…We found that detachment of these cells results in a noticeable upregulation of caspase inhibitors XIAP and cIAP2 both at the protein (Figure 1a and b) and mRNA ( Figure 1c and d) levels. We also observed that a significant upregulation of XIAP ( Figure 1e) and a relatively weak upregulation of cIAP2 (Figure 1f) occurs upon detachment of non-malignant anoikis-susceptible cells RIE-1, another cell line that was derived from rat intestinal epithelium (McFall et al, 2001;Rosen et al, 2001). We further tested whether detachment-induced upregulation of the IAPs takes place in human intestinal epithelial cells DKS-8 that were derived from human colorectal carcinoma cells DLD-1 by targeted disruption of the oncogenic K-ras allele (Shirasawa et al, 1993).…”

Section: Detachment Of Non-malignant Intestinal Epithelial Cells Trigmentioning

confidence: 59%

“…Furthermore, in support of our previous findings (Yan et al, 2005), we observed that nuclear fractions isolated from detached IEC-18 cells contained significantly higher levels of NF-kB than those derived from adherent cells (Figure 6b). It has to be noted here that in the present as well as most of the preceding studies, we deprived IEC-18 cells of adhesion to the ECM by culturing them above a layer of agarose (Rosen et al, 1998(Rosen et al, , 2000(Rosen et al, , 2001(Rosen et al, , 2002, whereas the recently observed detachment-induced activation of NF-kB was demonstrated for IEC-18 cells placed in a roller culture (Yan et al, 2005). Collectively, the results of the present study as well as our earlier work (Yan et al, 2005) indicate that detachment-induced activation of NF-kB does not depend on the method used for culturing these cells in suspension.…”

Section: Detachment-induced Upregulation Of the Iaps Is Nf-kb-dependentmentioning

confidence: 72%

“…Even though the activity of caspase-7 has not yet been tested in attached and detached IEC-18 cells, we found in the past that activation of caspase-3 does occur upon detachment of these cells (Rosen et al, 2001), suggesting that at least one of the known targets of the IAPs, such as caspase-3, contributes to the execution of anoikis. Effector caspases can be activated by the release of mitochondrial factors, such as cytochrome c, Omi/ HtrA2 and Smac/Diablo into the cytoplasm (Li et al, 1997;Du et al, 2000;Verhagen et al, 2000;Suzuki et al, 2001;Olson and Kornbluth, 2001;Verhagen et al, 2002;Tsujimoto, 2003;Gottfried et al, 2004).…”

Section: Detachment Of Non-malignant Intestinal Epithelial Cells Trigmentioning

confidence: 81%

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Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Liu

et al. 2006

Oncogene

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Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro-and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachmentdependent activation of the transcription factor nuclear factor-jB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.

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Transforming Growth Factor-α Prevents Detachment-induced Inhibition of c-Src Kinase Activity, Bcl-XLDown-regulation, and Apoptosis of Intestinal Epithelial Cells

Cited by 140 publications

References 57 publications

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

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