Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin

Abstract

We recently showed that extracellular matrix (ECM) proteins, which are abundant in desmoplastic pancreatic tumor, are as potent as growth factors in inhibiting apoptosis in pancreatic cancer (PaCa) cells. Here we show that fibronectin, a major ECM component, engages insulin-like growth factor-I receptor (IGF-IR) to inhibit PaCa cell death. We found that fibronectin-induced protection from apoptosis is fully mediated by IGF-IR and is independent of IGF-I. Pharmacologic and molecular inhibitions of IGF-IR stimulated apoptosis and prevented the prosurvival effect of fibronectin in PaCa cells. Our data indicate that fibronectin protects from apoptosis through trans-activation of IGF-IR. We showed that fibronectin stimulated complex formation between its receptor ␤3 integrin and protein-tyrosine phosphatase SHP-2. This process of complex formation, in turn, pre- Pancreatic cancer is the fourth most common cause of death in western countries with almost the same rate of incidence and mortality per year (1, 2). The disease is very resistant to radioand/or chemotherapies. One reason for that is the resistance of pancreatic cancer (PaCa) 2 cells to apoptosis (3).Pancreatic adenocarcinoma is a fibrotic tumor, which is characterized by a high level of extracellular matrix (ECM) proteins. ECM mediates adhesion and invasiveness of cancer cells. Cell survival also depends on adequate connections with ECM proteins through specific integrin receptors. We recently showed that ECM proteins are key mediators of PaCa cell survival (4, 5) and that detachment from ECM stimulates PaCa cell death. The mechanisms through which ECM proteins protect PaCa cells from death are not fully understood.Fibronectin is a major ECM protein of pancreatic adenocarcinoma; its receptors, ␤3 and ␤1 integrins, are up-regulated in pancreatic cancer cells (6). Fibronectin stimulates invasion and adhesion and markedly increases survival of pancreatic cancer cells (7,8).The importance of fibronectin and other extracellular matrix proteins in pancreatic cancer is underscored by several findings. Pancreatic adenocarcinoma is one of the most lethal of human cancers with a 5-year survival rate of less than 5% (9). This cancer has a characteristic of marked desmoplasia, which is a remarkable increase in extracellular matrix that infiltrates and envelopes the cancer (10). Importantly there is at least one report that demonstrates that greater amounts of intratumor extracellular matrix in pancreatic cancer patients are correlated with more aggressive disease and more rapid death (11). Finally recent studies in animal models of pancreatic cancer show that tumors grow more rapidly when the fibroblastic cells of the cancer called stellate cells are included in inocula with cancer cells (12). The addition of the stellate cells results in the experimental tumors taking on the characteristics of the human cancer with the extracellular matrix infiltrating and enveloping the cancer cells.In addition, another powerful mediator of PaCa cell survival is insulin-like growth fa...

Fibronectin Induces Endothelial Cell Migration through β1 Integrin and Src-dependent Phosphorylation of Fibroblast Growth Factor Receptor-1 at Tyrosines 653/654 and 766

“…Prior studies in endothelial cells have revealed that the FN-integrin complex is requisite for FN-induced chemotaxis and angiogenesis (45)(46)(47)(48), with both ␣v␤3 and ␣5␤1 implicated in this process (35,36,39). Another study on IGF-I receptor also found FN may transactivate this receptor via ␤3 integrin to protect cells from apoptosis (49). In the present study, perturbation of ␤1 integrin function significantly suppresses FGFR1 activation by FN, indicating a requisite role for ␤1 integrin in FN-induced RTK transactivation.…”

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

“…Studies by Goel et al (2004Goel et al ( , 2005 have shown that IGF-IR signaling and its mitogenic and transforming activities in prostate cancer cells are regulated by b1 integrin and this involves direct interaction between the two molecules. In addition, crosstalk between the integrin vitronectin receptor avb3 and the IGF-IR has been documented in various tumor cells (Clemmons and Maile, 2003), and the prosurvival effect of fibronectin in pancreatic carcinoma cells was shown to be mediated via IGF-IR and involve the b3 integrin (Edderkaoui et al, 2007). Our results are in line with some of these finding because they show that in cells with high type IV collagen expression, ligandinduced IGF-IR activation was potentiated, suggesting that crosstalk between a2b1 integrin and IGF-IR signaling in these cells may contribute to increased anoikis resistance and thereby metastasis.…”

Ellagic acid induces apoptosis through inhibition of nuclear factor kB in pancreatic cancer cells

“…Apoptosis parameters were measured as previously described [13][14][15][16] : Internucleosomal DNA fragmentation was measured by using Cell Death Detection ELISA Plus kit (Roche Molecular Biochemicals, Manheim, Germany) according to the manufacturer's instructions.…”