Effect of bile acids on butyrate-sensitive and -resistant human colon adenocarcinoma cells.
A controlled balance among cell proliferation, differentiation, and apoptosis is required for the maintenance of gastrointestinal mucosa; these processes are influenced by luminal components, such as butyrate and bile acids. Using butyrate-sensitive (BCS-TC2) and butyrate-resistant (BCS-TC2.BR2) human colon carcinoma cells, we wanted to establish whether colon carcinoma cells that acquire resistance to butyrate-induced apoptosis are also resistant to the cytotoxic effect of certain bile acids, contributing, in this way, to the progression of colon carcinogenesis. The effect of bile acids on BCS-TC2 cell viability is dose and time dependent and highly stereospecific. Quantification of the relative percentage of apoptotic cells and caspase-3 activity reveals that deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) induce apoptosis in BCS-TC2 cells. BCS-TC2.BR2 cells are consistently less sensitive to their cytotoxic effects, requiring concentrations to induce 50% inhibition (IC50) in cell viability of 740 microM and >1 mM for CDCA and DCA, respectively, compared with IC50 values of 310 and 540 microM for BCS-TC2 cells. DCA-treated BCS-TC2.BR2 cells show few apoptotic signs and no caspase-3 activation. On the other hand, CDCA-treated BCS-TC2.BR2 cells show caspase-3 activation and apoptotic features, although to a lower extent than BCS-TC2 cells. Our results, in an in vitro model system, point out that acquisition of butyrate resistance is accompanied by a partial resistance to the cytotoxic effects of bile acids, which may enhance the survival of tumorigenic cells.
Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain.
Pablo
P
Pérez-Ramos
Nieves
N
Olmo
Javier
J
Turnay
Emilio
E
Lecona
Gonzalo González
GG
de Buitrago
M Teresa
MT
Portolés
M Antonia
MA
Lizarbe
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D013997:Time Factors
D001647:Bile Acids and Salts; D002087:Butyrates; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases