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We previously demonstrated that fibronectin, a matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates non-small cell lung carcinoma (NSCLC) cell growth and survival. In this report, we explore the intracellular signals that mediate the effect of fibronectin by focusing on the mammalian target of rapamycin (mTOR), which is upregulated by PI3K/Akt signaling and downregulated by LKB1. In addition to stimulating the phosphorylation of Akt, fibronectin was found to induce the phoshorylation of p70s6K1 (p-p70s6K), a downstream target of mTOR, in a time- and dose-dependent manner in NSCLC cells (H157 and H1838). Rapamycin, an inhibitor of mTOR, blocked the baseline and fibronectin-induced phosphorylation of p70s6K and this was associated with inhibition of fibronectin-induced NSCLC cell growth as determined by thymidine incorporation. Fibronectin also inhibited the mRNA and protein expression of LKB1 as well as the phosphorylation of AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. In addition, 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, inhibited the phoshorylation and total content of p70s6K and abrogated fibronectin-induced phosphorylation of p70s6K. Finally, AICAR blocked the ability of fibronectin to stimulate NSCLC cell growth, and cotreatment of cells with AICAR and Rapamycin had a synergistic inhibitory effect. Altogether, this study suggests that fibronectin stimulates NSCLC cell growth, at least in part, through stimulation of the mTOR/AMPK signaling pathway.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]