Ursodeoxycholic Acid Exhibits Greater Inhibitory Effects on Cancerous HCT116 Colon Cells than on Noncancerous NCM460...

Background/Objectives: Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, exhibits anti-inflammatory effects and attenuates the process of colon carcinogenesis. Certain healthy diets increase colonic UDCA concentrations, but its anticancer mechanistic actions remain largely unknown. We hypothesize that UDCA preferentially inhibits cancerous colon cell proliferation with a minimal effect on noncancerous colon cells. Methods: With human noncancerous NCM460 colon cell and cancerous HCT116 colon cell culture models, we performed biochemical, western blotting, PCR array, cell cycle, apoptosis, and immunofluorescent assays to determine the effects of UDCA treatment on colon cell proliferation and the underlying molecular mechanisms. Results: The inhibitory potential of UDCA against cell proliferation (via cell cycle arrest and apoptosis) was 90% greater in cancerous HCT116 cells than noncancerous NCM460 cells when treated with UDCA (0 to 0.4 mM) for 48 h. In UDCA-treated HCT116 cells, we identified 18 genes with ≥80% change (compared to untreated cells) in mRNA levels out of 93 apoptotic genes which were involved in caspase, death receptor, and NFκB pathways. At the molecular level, 0.4 mM UDCA reduced the protein level of the proto-oncogenic c-Myc gene but increased the putative tumor suppressor p21 gene (≥100%) via the ERK1/2/c-Myc/p21 pathway, which regulates cell cycle and apoptosis. These data are consistent with lower c-Myc but higher p21 expression in normal colon tissues compared to cancerous colon tissues. Conclusions: Collectively, UDCA inhibits cancerous HCT116 colon cells to a higher degree than in noncancerous NCM460 colon cells through cell cycle and apoptosis involving ERK1/2/c-Myc/p21 signaling.