The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression

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.

Keywords: acetylcholine; bile acids; colon cancer; muscarinic ligands; muscarinic receptors.

Figure 1

Complex signaling following activation of muscarinic receptors in colon cancer cells. Subtype 3 muscarinic receptors (M₃R) are activated by bile acids (BA) or acetylcholine (ACh). The epidermal growth factor receptor (EGFR) is transactivated by heparin binding epidermal growth factor (HB-EGF), released from pro-HB-EGF by the actions of matrix metalloproteinase-7 (MMP-7), an enzyme whose expression and activation is also a result of M₃R activation (a ‘feed-forward’ mechanism). Signaling proceeds downstream via the extracellular related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase (PI3K) pathways, thereby inducing changes in the transcription of genes that promote cancer progression (cell proliferation, survival, migration and invasion).