Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-κB

Abstract

The extracellular matrix glycoprotein, fibronectin, influences a variety of cellular functions including adhesion, migration, survival, differentiation, and growth. Fibronectin has also been shown to increase the migration and proliferation of human lung carcinoma cells. However, the role of fibronectin in controlling lung airway epithelial cell phenotype remains unknown. Here, we demonstrate that fibronectin stimulates the proliferation of human bronchial epithelial cells (BEAS-2B and 16-HBE). Of note, fibronectin induced the mRNA and protein expression of c-Myc and cyclin D1, while it decreased the expressions of cyclin-dependent kinase inhibitor p21WAF-1/CIP1/MDA-6 (p21) and the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome ten (PTEN). Fibronectin also stimulated the phosphorylation of the phosphatidylinositol 3 kinase (PI3-K) downstream signal Akt. The inhibitor of PI3-K, Wortmannin, and anti-a5b1 integrin antibodies abrogated the effect of fibronectin on c-Myc, cyclin D1, p21, and PTEN expression. The stimulatory effect of fibronectin was mediated by nuclear factor kappaB (NF-jB) since fibronectin induced the expression of the p65 component of NF-jB and enhanced NF-jB DNA binding. Furthermore, we found that p65 small interfering RNA inhibited the effect of fibronectin on c-Myc, cyclin D1, p21, PTEN expression, and on fibronectin-induced cell proliferation. Finally, we found that fibronectin inhibits apoptosis by reducing DNA fragmentation and inhibiting the activities of caspases 3/7. Taken together, our findings demonstrate that fibronectin stimulates human bronchial epithelial cell growth and inhibits apoptosis through activation of NF-jB, which, in turn, increases the expression of c-Myc and cyclin D1 and decreases p21 and PTEN via a5b1 integrin-dependent signals that include PI3-K/Akt. Therefore, alternations in the extracellular matrix composition of the lung, with increased fibronectin, might promote epithelial cell growth and thereby contribute to oncogenesis in certain settings.

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

“…Plates were coated twice with 3 ml of polyHEMA dissolved in 95% ethanol (10 mg/ml), allowed to dry, and washed twice with phosphate-buff- ered saline before use. Compared with polyHEMA, we observed similar but less pronounced responses in cells grown on plastic or on plastic coated with polylysine (19). Plates coated with human fibronectin, collagen I, vitronectin, or soluble fibronectin (Sigma) were prepared by applying at 2 g/cm 2 the specified protein for 1 h at room temperature.…”

“…The fibronectin-induced protection from apoptosis in pancreatic cancer cells is mediated by the PI3K/Akt pathway (19). Indeed inhibition of PI3K by its inhibitor LY294002 increased DNA fragmentation in MIA PaCa-2 cells cultured on fibronectin (Fig.…”

Suppression of hepatocarcinoma model in vitro and in vivo by ECRG2 delivery using adenoviral vector

“…15 Its activation upregulates the levels of cyclin D1 and c-myc, promoting cell proliferation and suppressing cancer cell apoptosis. 16 In this study, downregulation of NF-kB by Ad-ECRG2 may contribute to suppression of cancer cell growth. E-cadherin is an important cell surface molecule for cell-cell interaction.…”

Inhalable siRNA: Potential as a Therapeutic Agent in the Lungs

“…These pro-oncogenic effects are mediated by PI3-kinase and NF-κB and can be blocked by the administration of an anti p65 siRNA leading to an antioncogenic effect. 50 RNAi may also provide opportunities for the treatment of CF, a genetic disorder exhibiting defective chloride transport. 51 The inability to transport chloride is a hallmark of CF resulting in a buildup of thick mucus in several organs, including the pancreas and the lungs, leading to malnutrition, chronic lung infection and damage.…”