Pde4a, a cyclic nucleotide phosphodiesterase, plays a crucial role in modulating intracellular levels of cyclic adenosine monophosphate (cAMP). By hydrolyzing cAMP, it is involved in multiple signaling pathways that impact various biological processes [5]. Targeting Pde4a shows promise in treating neurological disorders, mood disorders, inflammatory conditions, and cancer [5].

In ovarian cancer, low Pde4A expression promoted tumor progression. Knockdown of Pde4A significantly enhanced the proliferation, migration, and invasion of ovarian cancer cells, while overexpression had the opposite effect. Mechanistically, downregulation of Pde4A induced epithelial-mesenchymal transition (EMT) and nuclear translocation of Snail [1]. In hepatocellular carcinoma, higher Pde4a expression in tumor tissues was associated with poor prognosis, and it promoted metastasis by inducing EMT [4]. Psoralidin was shown to have a neuroprotective effect against MK-801-induced neurotoxicity, and it inhibited Pde4A [2]. Overexpression of PDE4A in T-cells restored proliferation, cytokine secretion, and cytotoxicity under immunosuppression, acting as an immune checkpoint inhibitor against cAMP-mediated immunosuppression [3].

In conclusion, Pde4a is vital in regulating cAMP-related signaling pathways, and its dysregulation is implicated in various diseases such as ovarian cancer, hepatocellular carcinoma, and neurodegenerative conditions. Studies using gene manipulation techniques, though not always in KO/CKO mouse models in the provided references, have revealed its role in processes like cell proliferation, migration, invasion, and immune regulation, offering potential therapeutic targets for these diseases.

References:

1. Wang, Jinlong, Gu, Qiuying, Liu, Yuexi, Li, Ruonan, Linghu, Hua. 2024. Low PDE4A expression promoted the progression of ovarian cancer by inducing Snail nuclear translocation. In Experimental cell research, 439, 114100. doi:10.1016/j.yexcr.2024.114100. https://pubmed.ncbi.nlm.nih.gov/38797258/

2. Uzunhisarcıklı, E. . Potential PDE4A inhibition-mediated neuroprotective effects of psoralidin. In European review for medical and pharmacological sciences, 28, 4546-4552. doi:10.26355/eurrev_202411_36913. https://pubmed.ncbi.nlm.nih.gov/39560930/

3. Schmetterer, Klaus G, Goldhahn, Katrin, Ziegler, Liesa S, Schwarzinger, Ilse, Marculescu, Rodrig. 2019. Overexpression of PDE4A Acts as Checkpoint Inhibitor Against cAMP-Mediated Immunosuppression in vitro. In Frontiers in immunology, 10, 1790. doi:10.3389/fimmu.2019.01790. https://pubmed.ncbi.nlm.nih.gov/31417563/

4. Peng, Yanghong, Li, Yijun, Tian, Yu, Ao, Guokun. 2018. PDE4a predicts poor prognosis and promotes metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. In Journal of Cancer, 9, 2389-2396. doi:10.7150/jca.24079. https://pubmed.ncbi.nlm.nih.gov/30026835/

5. Shamsi, Anas, Khan, Mohd Shahnawaz, Altwaijry, Nojood, Shahwan, Moyad, Yadav, Dharmendra Kumar. 2024. Targeting PDE4A for therapeutic potential: exploiting drug repurposing approach through virtual screening and molecular dynamics. In Journal of biomolecular structure & dynamics, , 1-13. doi:10.1080/07391102.2024.2308764. https://pubmed.ncbi.nlm.nih.gov/38287492/