trans-10,cis-12 Conjugated Linoleic Acid Induces Depolarization of Mitochondrial Membranes in HT-29 Human Colon Cancer Cells: A Possible Mechanism for Induction of Apoptosis
- 1 October 2009
- journal article
- Published by Mary Ann Liebert Inc in Journal of Medicinal Food
- Vol. 12 (5), 952-958
- https://doi.org/10.1089/jmf.2009.0056
Abstract
Conjugated linoleic acid (CLA), which is naturally present in a variety of foods such as milk fat and the meat of ruminant animals, has been demonstrated to exert chemoprotective effects in several tissues in experimental animals. CLA is a collective term, which denotes one or more positional and geometric isomers of octadecadienoic acid, with cis-9,trans-11 (c9t11) and trans-10,cis-12 CLA (t10c12) being the principal isomers in commercial preparations. We observed previously that physiological levels of CLA inhibited HT-29 cell growth, and the growth inhibitory effects of CLA were attributed to the effect of t10c12, but not c9t11. In the present study, we assessed the mechanisms by which physiological levels of CLA and t10c12 induce apoptosis in HT-29 cells. HT-29 cells were cultured for 3 days in serum-free medium in the presence of various concentrations of CLA (0-20 micromol/L) or t10c12 (0-4 micromol/L). Addition of CLA or t10c12 to culture medium resulted in a dose-dependent increase in the numbers of apoptotic cells. The results of western blot analysis of total cell lysates showed that CLA and t10c12 increased the levels of cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase but did not alter the levels of Bcl-2 family member proteins. However, these fatty acids were shown to increase the translocation of Bad and Bax to the mitochondria, increase mitochondrial membrane permeability, and induce the release of cytochrome c and Smac/Diablo from the mitochondria. In addition, CLA and t10c12 diminished Akt content and Akt phosphorylation. These findings indicate that physiological levels of t10c12 induce apoptosis in HT-29 colon cancer cells, which is mediated via mitochondrion-mediated events associated with a decline in Akt activity, an increase in the translocation of the pro-apototic Bad and Bax to the mitochondria, and the subsequent disruption of normal mitochondrial membrane potential.Keywords
This publication has 36 references indexed in Scilit:
- Role of Smac/DIABLO in cancer progressionJournal of Experimental & Clinical Cancer Research, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Influence of conjugated linoleic acid isomers on the metastasis of colon cancer cells in vitro and in vivoThe Journal of Nutritional Biochemistry, 2007
- The apoptosome: signalling platform of cell deathNature Reviews Molecular Cell Biology, 2007
- Dietary trans-10, cis-12 and cis-9,trans-11 Conjugated Linoleic Acids Induce Apoptosis in the Colonic Mucosa of Rats Treated with 1,2-DimethylhydrazineJournal of Medicinal Food, 2006
- High-fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography CohortThe American Journal of Clinical Nutrition, 2005
- Adenoma Growth Stimulation by the trans-10, cis-12 Isomer of Conjugated Linoleic Acid (CLA) Is Associated with Changes in Mucosal NF-κB and Cyclin D1 Protein Levels in the Min MouseJournal of Nutrition, 2003
- Dietary conjugated linoleic acid (CLA) induces apoptosis of colonic mucosa in 1,2-dimethylhydrazine-treated rats: a possible mechanism of the anticarcinogenic effect by CLABritish Journal of Nutrition, 2001
- The Hallmarks of CancerCell, 2000
- Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell deathCell, 1995