Inhibition of PI3K-AKT Signaling Blocks PGE2-Induced COX-2 Expression in Lung Adenocarcinoma
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Updated: Dec 9, 2025
Author Spotlight: Exploring the Role of Inflammation in the Co-occurrence of Primary Sjogren's Syndrome and Lung Adenocarcinoma
Published on: September 20, 2024
Jianjian Yang1, Xue Wang1, Yi Gao1
1Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Purpose:
Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE2) 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-PGE2 axis in tumors, it is necessary to revisit the mechanism underlying the protumor effect of COX-2-PGE2.
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 PGE2 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 PGE2 induces the expression of COX-2 at the mRNA and protein levels. Moreover, downregulation of COX-2 expression restrained PGE2-induced cancer cell proliferation and migration. Mechanistic analysis revealed that PGE2 stimulation activates the PKA-CREB and PI3K-AKT pathways. Downregulation of CREB expression abrogated PGE2-induced COX-2 expression. Moreover, inhibition of PI3K-AKT signaling suppressed the activation of CREB and PGE2-induced COX-2 expression. Specific inhibitors for PI3K and AKT suppressed COX-2 mRNA expression in ex vivo cultures of tumor specimens with PGE2.
Conclusion:
Simultaneous targeting of COX-2 and PI3K-AKT effectively suppressed PGE2-induced cell proliferation and migration and both acted in a synergistic manner. Targeting the COX-2-PGE2 positive feedback loop may be therapeutically beneficial to lung adenocarcinoma.
Insights
Targeting the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathway, alongside PI3K-AKT signaling, synergistically inhibits lung adenocarcinoma cell growth and migration. This dual approach offers a promising therapeutic strategy for lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) promote tumor growth, making them targets for cancer therapy.
- Previous clinical trials with COX-2 inhibitors for advanced lung cancer showed limited survival benefits.
- Understanding the underlying mechanisms of the COX-2-PGE2 axis is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of COX-2 and PGE2 in lung adenocarcinoma progression.
- To elucidate the signaling pathways involved in PGE2-induced COX-2 expression.
- To evaluate the therapeutic potential of targeting the COX-2-PGE2 axis, particularly in combination with PI3K-AKT inhibition.
Main Methods:
- Immunohistochemistry to assess COX-2 expression and prognostic value in lung adenocarcinoma.
- Quantitative PCR (qPCR) and Western blot to analyze gene and protein expression (COX-2, pAKT1/2/3, pErk1/2, pCREB).
- Cell proliferation (CCK-8) and migration (Transwell) assays to evaluate the effects of PGE2 and inhibitors.
- Ex vivo culture of tumor specimens to test the efficacy of PI3K and AKT inhibitors.
Main Results:
- COX-2 expression correlated with the pathological stage of lung adenocarcinoma.
- Exogenous PGE2 upregulated COX-2 expression in lung adenocarcinoma cell lines via PKA-CREB and PI3K-AKT pathways.
- Inhibition of PI3K-AKT signaling suppressed CREB activation and PGE2-induced COX-2 expression.
- Simultaneous inhibition of COX-2 and PI3K-AKT synergistically reduced cell proliferation and migration.
Conclusions:
- The COX-2-PGE2 axis forms a positive feedback loop in lung adenocarcinoma, involving PI3K-AKT and CREB signaling.
- Combined targeting of COX-2 and PI3K-AKT demonstrates synergistic efficacy in suppressing tumor cell proliferation and migration.
- This dual-targeting strategy represents a potentially beneficial therapeutic approach for lung adenocarcinoma.
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