Purpose: 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.