Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

dc.contributor.authorPfitzinger, Paulo L.
dc.contributor.authorFangmann, Laura
dc.contributor.authorWang, Kun
dc.contributor.authorDemir, Elke
dc.contributor.authorGuerlevik, Engin
dc.contributor.authorFleischmann-Mundt, Bettina
dc.contributor.authorBrooks, Jennifer
dc.contributor.authorD'Haese, Jan G.
dc.contributor.authorTeller, Steffen
dc.contributor.authorHecker, Andreas
dc.contributor.authorJesinghaus, Moritz
dc.contributor.authorJaeger, Carsten
dc.contributor.authorRen, Lei
dc.contributor.authorIstvanffy, Rouzanna
dc.contributor.authorKuehnel, Florian
dc.contributor.authorFriess, Helmut
dc.contributor.authorCeyhan, Guralp Onur
dc.contributor.authorDemir, Ihsan Ekin
dc.date.accessioned2023-02-21T12:40:44Z
dc.date.available2023-02-21T12:40:44Z
dc.date.issued2020-01-01
dc.description.abstractBackground Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.
dc.description.issue1
dc.description.issueDEC 24
dc.description.volume39
dc.identifier.doi10.1186/s13046-020-01796-4
dc.identifier.urihttps://hdl.handle.net/11443/2646
dc.identifier.urihttp://dx.doi.org/10.1186/s13046-020-01796-4
dc.identifier.wosWOS:000601538000001
dc.publisherBMC
dc.relation.ispartofJOURNAL OF EXPERIMENTAL \& CLINICAL CANCER RESEARCH
dc.subjectCholinergic
dc.subjectAcetylcholinesterase
dc.subjectPancreatic cancer
dc.subjectParasympathomimetics
dc.subjectElectroporation
dc.titleIndirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation
dc.typeArticle
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