CFTR Inhibitor And Activator Suppress PC-3Cells Multiplication And Migration And A Mouse Model Of Alcoholic Chronic Pancreatitis Associated With CFTR

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependentchloride channel, extensively expressed in the apical membrane of secretion and absorptionepithelial cells, which plays key roles in transepithelial fluid (water and salt) transport. Recentstudies indicated that CFTR function is closely related to tumorigenesis (such as prostatecarcinoma and pancreatic cancer) in reproductive system, pancreas, lung and liver. In thepresent study, we systematically investigated effects of CFTR inhibitors (CFTRinh-172andGlyH-101) and activator (resveratrol, RSV) on proliferation and migration in prostatecarcinoma cell line PC-3. Because it has been showed that CFTR function is also closelyrelated to the pathogenesis of chronic pancreatitis (CP), in the present study, we establishedmouse alcohol chronic pancreatitis model in Kunming mice to provide core technique basisfor further elucidation relationship between CFTR function and chronic pancreatitis.In the present study, we explored the role of CFTR inhibitors and activator in PC-3proliferation and migration by using MTT assay, wound healing assay and Hoechst stainingstudies. We found that:(1) CFTRinh-172significantly activated PC-3cell proliferation in adose-dependent way;(2) CFTRinh-172had little effect on cell migration, but it showedsynergy in PC-3cell migration inhibition;(3) GlyH-101dose-and time-dependentlyinhibited PC-3proliferation and migration, both effects are significant;(4) RSV significantlyinhibited both proliferation and migration in PC-3cell in dose-and time-dependent manner;(5) GlyH-101and RSV showed synergy effect in inhibition of PC-3cell proliferation andmigration;(6) Successfully established mouse alcohol chronic pancreatitis model in Kunmingmice.CFTRinh-172is the best CFTR inhibitor identified so far, which has been widely used inelucidation CFTR function in chlora toxin and enterotoxin-induced secretory diarrhea.CFTRinh-172has been under clinical study for the treatment of pulmonary edema fluidsecretion. CFTRinh-172is also regarded an ideal candidate drug for secretory diarrhea. Ourresults suggested potential risk in the clinical use of CFTRinh-172, further investigation areneeded.