Mitochondrial perturbation, oxidative stress and lysosomal destabilization are involved in 7beta-hydroxysitosterol and 7beta-hydroxycholesterol triggered apoptosis in human colon cancer cells.

Abstract

We reported previously that 7beta-hydroxysitosterol and 7beta-hydroxycholesterol induced apoptosis in Caco-2 cells. Apoptosis caused by 7beta-hydroxysitosterol but not by 7beta-hydroxycholesterol was related to a caspase-dependent process. In the present report, we compared the effects of both compounds on mitochondria integrity and on various modulators of apoptosis. When Caco-2 cells were exposed to both hydroxysterols, no changes in Bcl-2 and Bax expressions were detected indicating a Bcl-2/Bax-independent cell death pathway, whereas loss of mitochondrial membrane potential and cytochrome c release were observed. Endonuclease G expression and enhanced production of reactive oxygen species were detected in 7beta-hydroxycholesterol treated cells, but not with 7beta-hydroxysitosterol. Loss of mitochondrial membrane potential and cell death produced by both hydroxysterols were prevented by vitamin C. Lysosomal membrane integrity was altered with both hydroxysterols, but 7beta-hydroxysitosterol was significantly more active on than 7beta-hydroxycholesterol. Both hydroxysterols induced apoptosis by mitochondrial membrane permeabilization. However, 7beta-hydroxycholesterol exhibited a specific enhancement of oxidative stress and of endonuclease G expression despite its closely related chemical structure with 7beta-hydroxysitosterol. The two hydroxysterols exhibit different lipophilic properties which may explain their different biological effects.

• Authors: Stamatiki Roussi, Francine Gossé, Dalal Aoudé-Werner, Xin Zhang, Eric Marchioni, Philippe Geoffroy, Michel Miesch, Francis Raul
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 12 Issue 1 Pg. 87-96 (Jan 2007) ISSN: 1360-8185 [Print] Netherlands
• PMID: 17136497 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAX protein, human
• Hydroxycholesterols
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Sitosterols
• bcl-2-Associated X Protein
• hydroxysitosterol
• cholest-5-en-3 beta,7 alpha-diol
• Cytochromes c
• Endodeoxyribonucleases
• endonuclease G
• Ascorbic Acid

Topics

• Apoptosis (drug effects, physiology)
• Ascorbic Acid (pharmacology)
• Caco-2 Cells
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Cytochromes c (metabolism)
• Endodeoxyribonucleases (metabolism)
• Humans
• Hydroxycholesterols (pharmacology)
• Lysosomes (drug effects, metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Sitosterols (pharmacology)
• bcl-2-Associated X Protein (metabolism)