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 Mouse

Abstract

Conjugated linoleic acid (CLA) is a term used to describe the different conjugated isomers of linoleic acid. CLA has been found to be anticarcinogenic in mammary cancer, but its effects on colon carcinogenesis are still inconclusive. In this study, the isomer-specific effects of the cis-9, trans-11 and trans-10, cis-12 CLA isomers were investigated in the Min mouse model for intestinal carcinogenesis. The Min mice (n = 10/group) were fed either an AIN-93G control diet or a diet containing 1 g/100 g cis-9, trans-11 or trans-10, cis-12 CLA for 8 wk. The number and size of adenomas were measured and the proteins from the small intestinal tissues extracted for immunoblotting analysis. The number of adenomas did not differ, but the size of the adenomas was greater in the distal part of the small intestine in mice fed the trans-10, cis-12 isomer than in controls (1.19 +/- 0.16 vs. 0.94 +/- 0.21 mm, mean +/- SD, P < 0.01). The same isomer caused an increase in lipid peroxidation, measured as urinary 8-iso-prostaglandin (PG)F(2alpha). Nuclear p65 protein of the mucosal tissue was not detectable in the trans-10, cis-12 group, which differed (P < 0.05) from the control group. Cyclin D1, a target for the nuclear factor (NF)-kappaB pathway, was elevated in the trans-10, cis-12 group compared with the control group (P < 0.01), but cyclooxygenase-2 levels were not higher. There was no difference in beta-catenin protein levels between the groups. The results indicate that the trans-10, cis-12 isomer of CLA can act as a cancer promoter in colon carcinogenesis possibly through pathways affecting NF-kappaB and cyclin D1.

Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells

“…Furthermore, Yamasaki et al [13] reported that t10,c12-CLA but not c9,t11-CLA showed a potent cytotoxic effect on the rat hepatoma cells by activating the apoptotic pathway. The higher anticarcinogenic effect of t10,c12-CLA than c9,t11-CLA has been also found in breast cancer cells [14] and in min mouse model [15].…”

Biological effects of conjugated linoleic acids in health and disease

“…Another study examined the role of purified isomers fed at 1% of the diet on Min mouse model of intestinal carcinogenesis and found that t10c12 isomer promoted carcinogenesis instead of inhibiting it. The authors suggested that activation of NF-nB pathway and cyclin D1 could be involved in the cancer-promoting effect of t10c12 isomer [124]. The same study also showed that t10c12 significantly elevated 8-iso-prostaglandin PGF 2a levels, which is a marker for lipid peroxidation.…”

“…In vivo A tumor load and lung metastases in SCID mice [154] In vivo X growth and development of prostate tumor cells [155] A in vitro t10c12 and c9t11 through different pathways but t10c12 was more antiproliferative than c9t11 [151,152] Breast cancer In vivo A chemically induced carcinogenesis in rats [10,143] In vivo A transplantable breast cancer tumor cells and metastasis [144,145] In vitro A cell cycle in MCF-7 breast cancer cells [130] In vitro A growth-suppression of MCF-7 breast cancer cells by CLA or isomers [133 -136] In vitro A VEGF-A in MCF-7 cells cultured with human breast stromal cells by CLA isomers [142] CLA isomers A proliferation in MCF-7 cells through different mechanisms [138] CLA isomers have antiestrogenic properties in MCF-7 cells [139] In humans, CLA content of diet or adipose tissue not associated with lower risk of breast cancer [146,147] No association between dietary or serum CLA and breast cancer risk [149,150] Gastrointestinal cancer/colon cancer A BAP-induced forestomach tumorigenesis by CLA and isomers (98% purity) [8,120] A chemically induced colon carcinogenesis [11,121,123,125,127] X azoxymethane induced carcinogenesis [122,124] t10c12 carcinogenesis in Min mouse model [124] A metastasis of human gastric and colon cancer cells [126] A HT-29 colon cancer cell growth [113,114] t10c12 Caco2 and HT-29 colon cancer cells but c9t11 does not [115 -117] recent study in genetically obese C57BL/6 lep ob /lep ob mice, intake of diet supplemented with 1.5% CLA mix or CLA enriched in t10c12 for 2 weeks elevated fasting glucose and insulin levels, and failed the glucose tolerance test [44]. However, when diet was continued for 10 weeks, CLA had beneficial effects on both glucose...…”

Mechanisms of body fat modulation by conjugated linoleic acid (CLA)

“…Activation of NFjB by CLA has been reported but results are not consistent; CLA decrease NFjB activation when stimulated by lipopolysaccharide, TNF-a, or interferon-c, but others reports showed either no effect or increased NFjB activation by CLA, particularly by the trans-10,cis-12 isomer (Bassaganya-Riera et al, 2004;Cheng, Lii, Chen, Lin, & Liu, 2004;Chung, Brown, Provo, Hopkins, & McIntosh, 2005;Li et al, 2005;Loscher et al, 2005; Rajakangas, Basu, Salminen, & Mutanen, 2003;Ringseis, Saal, Muller, Steinhart, & Eder, 2004;Schleser, Ringseis, & Eder, 2005;Sheu et al, 2006). Chung, Brown, Provo, et al (2005) recently demonstrated that trans-10,cis-12 CLA activates NFjB both in stromal vascular cells and adipocytes but with different roles.…”