LB916 Effects of the platelet-activating factor-receptor and microRNA-149 in lung cancer growth and therapy effectiveness

Abstract

Lung cancer remains the leading cause of cancer-related deaths, with low response rates to the current treatment options, indicating the need to explore potential factors, involved in lung cancer growth or impeding the efficacy of therapeutic agents. Studies, including ours, have shown the critical roles of a G-protein coupled, platelet-activating factor-receptor (PAF-R) signaling in augmenting tumor growth or limiting therapy effectiveness in various experimental cancer models. While several mechanisms of the PAF-R pathway have been proposed, its effect with microRNAs (miRs) has not been studied. In particular, while miR-149 has been shown to play oncogenic roles in other cancer types, it functions as a tumor suppressor in lung cancer. The current study aimed to determine the effects of PAF-R and miR-149 in lung cancer growth and therapy effectiveness. We first evaluated the functional significance of PAF-R and miR-149 using A549 and H1299 human non-small cell lung cancer (NSCLC) cell lines as tools. These tumor lines express endogenous PAF-R and miR-149, and PAF-R activation by PAF agonist (CPAF) significantly increased-, whereas miR-149 mimic transfection inhibited cell proliferation in a dose-dependent manner. Interestingly, miR-149 mimic significantly attenuated CPAF-mediated increased proliferation of A549 cells, as also confirmed by miR-149 expression analysis via qPCR. We then examined PAF-R and miR-149 effects on currently used targeted therapy (i.e., erlotinib and gefitinib) responses. Both these agents inhibited the survival of A549 and H1299 cell lines in a dose- and time-dependent manner. While CPAF significantly blocked erlotinib and gefitinib (at ∼IC50 dose)-mediated decreased cell proliferation, PAF-R antagonist and miR-149 mimic did not exert any effects. While additional studies are needed, these findings indicate that miR-149 overcomes PAF-R-mediated increased cell proliferation effect, and PAF-R activation attenuates cytotoxic response of targeted therapy.