cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

• Published in: Journal of hematology and oncology Vol. 17; no. 1; p. 5
• Main Authors: Zhang, Hongying, Liu, Yongliang, Liu, Jieya, Chen, Jinzhu, Wang, Jiao, Hua, Hui, Jiang, Yangfu
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.01.2024; BioMed Central; BMC
• Subjects: Adenosine; Adenylate cyclase; Adenylic acid; Angiogenesis; Apoptosis; Autoimmune diseases; B cells; cAMP; cAMP-dependent protein kinase; Cancer; Cell cycle; Cell death; Cell growth; Cell proliferation; Cell survival; Cyclic adenylic acid; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; Cytokines; Development and progression; Environmental factors; Enzymes; Epstein-Barr virus; Exchange protein activated by cAMP; Extracellular matrix; Forskolin; Growth factors; Guanine Nucleotide Exchange Factors - metabolism; Health aspects; HIV; Homeostasis; Hormones; Human immunodeficiency virus; Humans; Immunotherapy; Ion channels; Kinases; Neoplasms; Peptides; Phosphatase; Phosphorylation; Physiology; PKA; Protein kinase A; Protein kinases; Proteins; Review; Signal Transduction; Stromal cells; Transcription factors; Tumor Microenvironment; Tumor-infiltrating lymphocytes; Tumorigenesis; Tumor microenvironment; Immunotherapy; PKA; cAMP; cAMP-dependent protein kinase; Exchange protein activated by cAMP; Cancer
• DOI: 10.1186/s13045-024-01524-x
• ISSN: 1756-8722

Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.