Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity.
BACKGROUND
There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA), a putative chemopreventive agent, exhibited distinct biological effects, yet appeared to act on some of the same signaling molecules. The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA.


METHODS
To determine whether there was an overlap in activation of signaling pathways by DCA and UDCA, we mutagenized HCT116 cells and then isolated cell lines resistant to UDCA induced growth arrest. These lines were then tested for their response to DCA induced apoptosis.


RESULTS
We found that a majority of the cell lines resistant to UDCA-induced growth arrest were also resistant to DCA-induced apoptosis, implying an overlap in DCA and UDCA mediated signaling. Moreover, the cell lines which were the most resistant to DCA-induced apoptosis also exhibited a greater capacity for anchorage independent growth.


CONCLUSIONS
We conclude that UDCA and DCA have overlapping signaling activities and that disregulation of these pathways can lead to a more advanced neoplastic phenotype.
Powell
Ashley A
AA
Cancer Biology Interdisciplinary Program, University of Arizona, Arizona Cancer Center, Tucson, AZ 85724, USA. ashleypowell@stanford.edu
Akare
Sandeep
S
Qi
Wenqing
W
Herzer
Pascal
P
Jean-Louis
Samira
S
Feldman
Rebecca A
RA
Martinez
Jesse D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003840:Deoxycholic Acid / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000517:prevention & control*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; C010471:hyodeoxycholic acid; D011065:Poly(ADP-ribose) Polymerases