Abstract

Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells.

Highlights

  • Lung cancer is currently the second most prevalent type of cancer in both men and women in the United States, which continues to be a major health and socioeconomic issues [1,2,3]

  • Our studies demonstrate that targeted therapies-induced reactive oxygen species (ROS) generation is significantly reduced by NAC and WEB2086 compounds, similar to as observed by CPAF treatment (Figure 1B)

  • These studies confirmed that targeted therapies induce ROS generation, and suggest the role of the platelet-activating factor-receptor (PAFR) signaling in mediating this effect

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Summary

Introduction

Lung cancer is currently the second most prevalent type of cancer in both men and women in the United States, which continues to be a major health and socioeconomic issues [1,2,3]. Several risk factors have been known to be associated with lung carcinogenesis, including environmental factors and pollutants such as smoking and arsenic exposure, etc., as well as genetic factors [4,5,6]. While lung cancer cases have been documented in non-smoking patients, smoking remains the most common contributing factor as long-term exposure to smoking has been shown to induce dysregulation and disruption in healthy lungs [7,8,9]. Non-small cell lung carcinoma (NSCLC) accounts for the majority of the cases diagnosed compared to a less prevent small cell lung carcinoma (SCLC) [10,11]. Depending upon the lung cancer stages, the treatment options include surgical resection, chemotherapy, radiation therapy, targeted and immune-based approaches, as well as a combination of two or more therapeutic agents [15,16,17,18,19]

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