Targeting M3 Muscarinic Receptors for Colon Cancer Therapy

Abstract

Background: Expression and activation of subtype-3 muscarinic receptors (M3R) plays an important role in the progression of colorectal neoplasia.

Method: Herein, we describe the role of muscarinic receptors in colon cancer, focusing specifically on M3R, illustrate how M3R over-expression and activation of post-receptor signaling pathways potentiates tumor progression, and explore the efficacy and safety of a variety of therapeutic approaches that can target the molecules involved.

Results: Colon cancers overexpress M3R mRNA (CHRM3) and protein, and post-M3R signaling stimulates cell proliferation. Post-M3R signal transduction is complex, involving interplay between epidermal growth factor receptors (EGFR)/ERK and protein kinase C (PKC)/p38 mitogen-activated protein (MAP) kinase signaling pathways. In particular, the development of an invasive and metastatic phenotype requires that these signaling interactions augment cellular release of a key collagenase, matrix metalloproteinase-1 (MMP1). Blocking either M3R activation or post-M3R signaling attenuates MMP1 release and colon cancer invasiveness.

Conclusion: Parsing the complexities of these signaling interactions is important, not only to understand these mechanisms of cancer initiation and progression, but also to develop novel treatment modalities. Since the vast majority of persons with colon cancer die from disseminated disease, preventing or reversing metastatic spread of cancer cells by targeting M3R, post-M3R signaling, or MMP1 has therapeutic potential.

Keywords: Colon cancer; EGFR; M3R; MMP inhibitor; MMP1; colon cancer; matrix metalloproteinase; muscarinic receptor..

Fig. (1).

M3R-related signaling pathways with sites of action for inhibitors. PKC, protein kinase C; MAPK, mitogen-activated protein kinase; P13K phosphatidylinositol-3’-OH kinase; EGFR, epidermal growth factor receptor; RSK, ribosomal S6 kinase; MMP1, matrix metalloproteinase-1; FOXD3, forkhead box D3.