Abstract
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.
Highlights
Lung cancer, especially non-small cell lung cancer (NSCLC) (Liu et al, 2018), is a common malignant tumor that seriously damages human health and life (Ferlay et al, 2015; Chen et al, 2016; Shen et al, 2017)
Considering that prostaglandin E2 (PGE2) is the major product catalyzed by prostaglandin-endoperoxide synthase-2 (PTGS2), we speculated that PTGS2 might play important roles in the chemoresistance of platinumbased therapy
We revealed that cisplatin induced PTGS2 expression through the reactive oxygen species (ROS)-ERK1/2-NF-κB signaling axis, and PGE2 might strengthen PTGS2 expression through the PGE2-prostaglandin EP receptors (EPs)-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells via mediating the augmentation effects of cisplatin on B cell lymphoma 2 (BCL2) expression and the subsequent impairment of cell apoptosis
Summary
Especially non-small cell lung cancer (NSCLC) (Liu et al, 2018), is a common malignant tumor that seriously damages human health and life (Ferlay et al, 2015; Chen et al, 2016; Shen et al, 2017). It is the most malignant tumor with the highest morbidity and mortality worldwide. Mechanisms including reduction of drug uptake, enhancement of DNA repair, and detoxification efficacy have been proposed to be responsible for the acquired resistance to cisplatin-based chemotherapy (Galluzzi et al, 2014).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
