Fish Oil Inhibits Human Lung Carcinoma Cell Growth by Suppressing Integrin-Linked Kinase

We previously showed that synthetic peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands inhibit non-small cell lung carcinoma (NSCLC) cell growth through multiple signaling pathways. Here, we show that dietary compounds, such as fish oil (which contains certain kinds of fatty acids like omega 3 and omega 6 polyunsaturated fatty acids), also inhibit NSCLC cell growth by affecting PPAR gamma and by inhibiting the expression of integrin-linked kinase (ILK). Exogenous expression of ILK overcame, whereas silencing ILK enhanced the inhibitory effect of fish oil on cell growth. The inhibitor of p38 mitogen-activated protein kinase, SB239023, abrogated the inhibitory effect of fish oil on ILK expression, whereas the inhibitor of extracellular signal-regulated kinase, PD98059, had no effect. Transient transfection experiments showed that fish oil reduced ILK promoter activity, and this effect was abolished by AP-2 alpha small interfering RNA and SB239023 and by deletion of a specific portion of the ILK gene promoter. Western blot analysis and gel mobility shift assay showed that fish oil significantly induced AP-2 alpha protein expression and AP-2 DNA-binding activity in the ILK gene promoter and that this was dependent on PPAR gamma activation. Blockade of AP-2 alpha abrogated the effect of fish oil on ILK expression and on cell growth, whereas exogenous expression of AP-2 alpha enhanced cell growth in the setting of fish oil exposure. Taken together, these findings show that fish oil inhibits ILK expression through activation of PPAR gamma-mediated and p38 mitogen-activated protein kinase-mediated induction of AP-2 alpha In turn, this leads to inhibition of NSCLC cell proliferation. This study unveils a novel mechanism by which fish oil inhibits human lung cancer cell growth. (Mol Cancer Res 2009;7(1):108-17)