Cholinergic Targets in Lung Cancer

Abstract

Background Lung cancers express an autocrine cholinergic loop in which secreted acetylcholine can stimulate tumor growth through both nicotinic and muscarinic receptors. Because activation of mAChR and nAChR stimulates growth; tumor growth can be stimulated by both locally synthesized acetylcholine as well as acetylcholine from distal sources and from nicotine in the high percentage of lung cancer patients who are smokers. The stimulation of lung cancer growth by cholinergic agonists offers many potential new targets for lung cancer therapy. Methods The potential of cholinergic targets to inhibit lung cancer growth can be evaluated by use of antagonists, agonists, gene silencing and gain of function. Results Cholinergic signaling can be targeted at the level of choline transport; acetylcholine synthesis, secretion and degradation; and nicotinic and muscarinic receptors. In addition, the newly describe family of ly-6 allosteric modulators of nicotinic signaling such as lynx1 and lynx2 offers yet another new approach to novel lung cancer therapeutics. Conclusions Each of these targets has their potential advantages and disadvantages for the development of new lung cancer therapies which are discussed in this review.

Targeting Phospholipid Metabolism in Cancer

“…In these cancers, ACh acts as an autocrine or local paracrine growth factor that stimulates tumor growth, with muscarinic cholinergic receptor subtype M3 or nicotinic cholinergic receptors functioning as its receptors (147, 149, 150), which is indicated in Figure 6. However, the free choline transported into some cells for this non-neuronal ACh synthesis is not dependent on CHT1 transport (150–152). Knockdown of CTL4, but not other genes in the CTL family, in both lung and colon cancer cells significantly decreased ACh secretion and cell growth, suggesting that CTL4 is a reasonable target for certain types of cancer therapy without affecting neuronal ACh synthesis (150, 153).…”

α9‐ and α7‐containing receptors mediate the pro‐proliferative effects of nicotine in the A549 adenocarcinoma cell line

“…It was originally believed that nAChRs are only present in the nervous system, but it has now been shown that they are expressed in numerous cell types. In particular, they are expressed in airway epithelial cells, which synthesize, store, process and secrete ACh (reviewed in Wessler and Kirkpatrick, ; Spindel, ). When lung cancer arises from airway epithelial cells, they continue to express nAChRs, and their growth is stimulated by nicotine (reviewed in Tournier and Birembaut, ).…”

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

“…Many studies recently have revealed that ACh also plays a non-neuronal role in some physiological and pathological process including inflammatory diseases89, functional bowel disorders1011, as well as several kinds of cancer1213. Several reports have indicated that ACh could act as a potential growth factor to stimulate cancer cell proliferation in lung cancer14, breast cancer15, colon cancer16 et al . Furthermore, ACh could also be synthesized and considered as auto-stimulating growth factor in some types of cancer1718.…”