A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation.
Ursodeoxycholic acid (UDCA), a relatively nontoxic bile acid, enhanced the apoptotic response of tumor cells to both photosensitizers that cause photodamage to Bcl-2 and to the nonpeptidic Bcl-2/Bcl-x(L) antagonist HA14-1. The latter agent binds to the surface pocket formed by the BH1, BH2 and BH3 domains of Bcl-2 and Bcl-x(L). Fluorescence polarization studies indicated that affinity of HA14-1 for Bcl-2 was enhanced in the presence of UDCA. Moreover, Bcl-2 photodamage was promoted by UDCA using a photosensitizing agent with affinity for the endoplasmic reticulum, a site of Bcl-2 localization. Fluorescence resonance energy transfer (FRET) studies revealed that the proximity of Bcl-2 to a hydrophobic photosensitizing agent embedded in liposomes was enhanced by UDCA. Since photodamage will occur only if a protein is in close contact with a photosensitizing agent, we propose that these findings support the hypothesis that UDCA causes a conformational change in Bcl-2, promoting HA14-1 binding and enhancing affinity for certain membrane-bound photosensitizers.
Castelli
M
M
Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Reiners
J J
JJ
Kessel
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005454:Fluorescence Polarization; D031541:Fluorescence Resonance Energy Transfer; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008968:Molecular Conformation; D009570:Nitriles / Q000494:pharmacology*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D001578:Benzopyrans; D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; D008081:Liposomes; D009570:Nitriles; D017319:Photosensitizing Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; C052617:Bcl2 protein, mouse; D014580:Ursodeoxycholic Acid