**3. Link between autophagy and the nicotinic cholinergic system**

The role of neurology genes in the progression and metastasis of cancer in general has been emphasized recently. In many reviews, Hildegard M. Schuller established the theory that modulation of the autonomic nervous system is responsible for driving cancer development, progression, and resistance to chemotherapy not only in non–small-cell lung cancer and pancreatic ductal adenocarcinoma but also in other cancers [43–48].

She anticipated the different modifiable risk factors of PDAC development, including smoking, chronic psychological stress, and habitual ingestion of alcohol, to act mostly via the sensitization (α7nAChR) and desensitization (α4nAChR) of nAChRs that drive the expression of proteins, which regulate the synthesis and release of catecholamines and GABA and result in the hyperactivity of Gs-mediated cAMP signaling [47]. α7nAChR activation is responsible for the production of stress neurotransmitters, which are known to promote cancer features, as well as of serotonin, dopamine, and glutamate, while the desensitization of α4nAChR is the main reason for reduced GABA levels, which is known to be a protective neurotransmitter [45]. This is believed to disturb the normal equilibrium and homeostasis of the signaling neurotransmitters in favor of cancer development, progression, and reduced responsiveness to treatment [44].

A link between the nicotinic cholinergic system and autophagy can be thought as follows: in one study, nicotine hindered the macrophage clearance of mycobacterium tuberculosis via inhibition of autophagosome formation in infected T helper cells and macrophages [49]. In another study, nicotine enhanced the proteasome activity and the total protein ubiquitination as well as autophagy as was proven by the occurrence of autophagic vacuoles and increased MAP LC3-II at protein level. These mechanisms help in the downregulation of connexin 43 and limit the communication in endothelial cells based on the involvement of nAChR α4β2 and α3β2, but not α7 [50]. Jeong et al. have shown that melatonin's neuroprotective effects against prion-mediated neural damage are owing to the activation of autophagy as an outcome of α7nAchR regulation [51].
