OncoTargets and Therapy (Aug 2020)
Inhibition of PI3K-AKT Signaling Blocks PGE2-Induced COX-2 Expression in Lung Adenocarcinoma
Abstract
Jianjian Yang, Xue Wang, Yi Gao, Can Fang, Fan Ye, Bing Huang, Lequn Li Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Lequn LiDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, Hubei 430030, People’s Republic of ChinaTel + 86-15172330682Email [email protected]: Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE 2) possess tumor-promoting activity, and COX-2 is considered as a candidate for targeted cancer therapy. However, several randomized clinical trials using COX-2 inhibitors to treat advanced lung cancer have failed to improve survival indices. To employ a more effective therapeutic strategy to inhibit the COX-2-PGE 2 axis in tumors, it is necessary to revisit the mechanism underlying the protumor effect of COX-2-PGE 2.Patients and Methods: Immunohistochemistry was used to predict the expression and prognostic value of COX-2 in lung adenocarcinoma samples. The mRNAs or proteins expression of COX-2, pAKT1/2/3, pErk1/2 and pCREB were detected after different treatments by qPCR or Western blot. The impacts of PGE 2 and some inhibitors on cell proliferation and migration ability were verified by CCK-8 and transwell assays, respectively.Results: In this study, we first confirmed that COX-2 expression in tumor specimens is associated with the pathological stage of the disease. Next, using lung adenocarcinoma cell lines, we found that exogenous PGE 2 induces the expression of COX-2 at the mRNA and protein levels. Moreover, downregulation of COX-2 expression restrained PGE 2-induced cancer cell proliferation and migration. Mechanistic analysis revealed that PGE 2 stimulation activates the PKA-CREB and PI3K-AKT pathways. Downregulation of CREB expression abrogated PGE 2-induced COX-2 expression. Moreover, inhibition of PI3K-AKT signaling suppressed the activation of CREB and PGE 2-induced COX-2 expression. Specific inhibitors for PI3K and AKT suppressed COX-2 mRNA expression in ex vivo cultures of tumor specimens with PGE 2.Conclusion: Simultaneous targeting of COX-2 and PI3K-AKT effectively suppressed PGE 2-induced cell proliferation and migration and both acted in a synergistic manner. Targeting the COX-2-PGE 2 positive feedback loop may be therapeutically beneficial to lung adenocarcinoma.Keywords: PGE 2, COX-2, AKT, EP receptor, lung adenocarcinoma
