Abstract
Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and protein are over-expressed in colon cancer, and M3R can be activated by both traditional (e.g., acetylcholine) and non-traditional (e.g., bile acids) muscarinic ligands. In this review, we weigh the data supporting a prominent role for key protein kinases downstream of M3R activation in promoting colon cancer progression and dissemination. Specifically, we explore the roles that downstream activation of the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK), protein kinase C, p38 MAPK, and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways play in mediating colon cancer cell proliferation, survival, migration and invasion. We assess the impact of M3R-stimulated induction of selected matrix metalloproteinases germane to these hallmarks of colon cancer progression. In this context, we also critically review the reproducibility of findings derived from a variety of in vivo and in vitro colon cancer models, and their fidelity to human disease. Finally, we summarize the therapeutic potential of targeting various steps from ligand-M3R interaction to the activation of key downstream molecules.
Highlights
Colorectal carcinoma (CRC) is a leading cause of cancer mortality; approximately 1.4 million new cases were diagnosed worldwide in 2012 with 693,900 deaths in the same year [1]
In H508 human colon cancer cells, bile acids increased cell proliferation, an effect blocked by atropine and inhibitors of epidermal growth factor receptors (EGFR), confirming that proliferative effects are mediated by interplay between two very different classes of receptors, G
The M3 muscarinic receptor subtype is over-expressed in colorectal carcinomas, where it plays an important role in key neoplastic processes including cell proliferation, survival, invasiveness, and metastatic spread
Summary
Colorectal carcinoma (CRC) is a leading cause of cancer mortality; approximately 1.4 million new cases were diagnosed worldwide in 2012 with 693,900 deaths in the same year [1]. Despite improving screening rates and the availability of novel treatments, CRC remains the second and third leading cause of cancer death in the United States for men and women, respectively. Complex signaling pathways govern these processes, and newer chemotherapeutic approaches are being developed to target these pathways. An example of such a promising target that resulted in new therapies over the past decade, is epidermal growth factor receptor (EGFR) signaling. We explore the potential for leveraging these advances in knowledge to develop novel therapeutic approaches to target these pathways
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