The Role of PDE3A in Cancer

Objective: PDE3A is a key member of the cyclic nucleotide phosphodiesterase family. By modulating intracellular cAMP and cGMP levels, it participates in diverse physiological processes such as platelet activation, cardiac function, oocyte maturation, and vascular smooth muscle cell proliferation. Recent studies have revealed that PDE3A also plays critical roles in multiple malignant tumors. This study aims to investigate the regulation of PDE3A expression, its role in cancer, and its potential as a therapeutic target, with a particular focus on its impact on tumor cell proliferation, metastasis, and resistance to chemotherapy. Methods: A systematic review of 221 PubMed-indexed articles published through April 2, 2025, was conducted to examine the expression and functional mechanisms of PDE3A in various cancer types. This study explored the regulation of PDE3A expression in cancer cells, its role in cell signal transduction, and its involvement in tumor initiation, progression, metastasis, and chemotherapy resistance. Additionally, it explored the inhibition of PDE3A and its potential as a therapeutic target for cancer treatment. Results: PDE3A is aberrantly overexpressed in various cancers, particularly in gastrointestinal stromal tumors, hepatocellular carcinoma, and breast cancer. Its expression is regulated at multiple levels, including DNA mutations (e.g., Y497C), DNA methylation, transcription factors (SFPQ, MYBL2), epigenetic modifications (such as FSCN1-mediated alternative splicing, m6A modification by METTL3, microRNAs targeting PDE3A), and post-translational modification (14–3–3 protein). PDE3A contributes to cancer stem cell characteristics, metastasis, and chemotherapy resistance through both cAMP/PKA-dependent and cAMP/PKA-independent pathways, including the NF-κB, YAP/TEAD, and β-catenin/ID3 signaling axes. Notably, PDE3A can form a molecular gel-dependent complex with SLFN12 to induce apoptosis, a mechanism targeted by novel drugs such as OPB-171775 and BAY 2666605. Furthermore, combining PDE3A inhibitors (e.g., cilostazol) with existing chemotherapy agents (e.g., imatinib) significantly enhances antitumor efficacy, particularly in refractory tumors like gastrointestinal stromal tumors, demonstrating a strong synergistic effect. Conclusion: PDE3A plays a pivotal role in tumorigenesis and cancer progression, with aberrant expression strongly associated with tumor proliferation, metastasis, and resistance to chemotherapy. As a therapeutic target, PDE3A holds significant potential. The development of PDE3A inhibitors or molecular adhesive agents may offer novel treatment strategies, particularly for chemotherapy-resistant tumor types.