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Abstract

Cholecystokinin (CCK), a known mitogen for the exocrine pancreas, is shown to activate 70-kDa S6 kinase in isolated pancreatic acini. In this study, we examined the kinetics and cellular mechanisms of CCK-induced p70 S6 kinase activation in vivo and in vitro. Fasted mice were intraperitoneally injected with 0.01-10 microg/kg CCK analoge cerulein. Cerulein caused a concentration-dependent activation of p70 S6 kinase, with the maximal effect at 1-10 microg/kg. After 1 microg/kg cerulein administration, the kinase activity was increased at 5 min, peaked at 10 min, and subsequently decreased. Cerulein also caused a rapid and transient activation of Src. Prior administration of the tyrosine kinase inhibitor herbimycin A compeletely inhibited cerulein-induced Src activation, while the inhibition of p70 S6 kinase activity was partial. Similar results were obtained with pancreatic acinar cell line AR42J cells. These results suggest that tyrosine kinases, including Src as a possible candidate, are partly implicated in the signaling pathway of CCK-induced p70 S6 kinase activation in the exocrine pancreas.

Zonation of Pancreatic Acinar Cells in Diabetic Mice

“…In contrast, our study supports the role of CCK, a central secretagogue of acinar cells, as a facilitator of acinar cell zonation via three lines of evidence: (1) Cck was the most highly induced ligand in the db/db islets ( Figures 3 A–3C); (2) elevated CCK levels in acinar cell cultures elicit transcriptional changes that overlap the peri-islet acinar gene expression signature that we observed in vivo , an overlap that was not observed when treating cells with insulin ( Figure 3 E); and (3) a decline in intra-islet Cck expression in older mice coincided with a decrease in acinar zonation ( Figures 3 C, 3F, and 3G). Moreover, CCK is a potent activator of the mTOR pathway, as previously shown in AR42J cells ( Inushima et al., 2001 ), which could also account for our observed increase in mTOR activity in peri-islet acinar cells in db/db mice ( Figures 3 H and 3J). Beta cell-secreted CCK has been shown to accelerate the progression of pancreatic ductal cancer in obese mice, supporting the ability of CCK to diffuse and affect the exocrine parenchyma ( Chung et al., 2020 ).…”