We previously showed that synthetic
peroxisome proliferator-activated receptor gamma (
PPARgamma)
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 omega3 and omega6
polyunsaturated fatty acids), also inhibit NSCLC cell growth by affecting
PPARgamma 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-2alpha
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-2alpha
protein expression and AP-2
DNA-binding activity in the ILK gene promoter and that this was dependent on
PPARgamma activation. Blockade of AP-2alpha abrogated the effect of
fish oil on ILK expression and on cell growth, whereas exogenous expression of AP-2alpha enhanced cell growth in the setting of
fish oil exposure. Taken together, these findings show that
fish oil inhibits ILK expression through activation of
PPARgamma-mediated and
p38 mitogen-activated protein kinase-mediated induction of AP-2alpha. 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.