Antiproliferative Action of Conjugated Linoleic Acid on Human MCF-7 Breast Cancer Cells Mediated by Enhancement of Gap Junctional Intercellular Communication through Inactivation of NF-κB

Abstract

The major conjugated linoleic acid (CLA) isomers, c9,t11-CLA and t10,c12-CLA, have anticancer effects; however, the exact mechanisms underlying these effects are unknown. Evidence suggests that reversal of reduced gap junctional intercellular communication (GJIC) in cancer cells inhibits cell growth and induces cell death. Hence, we determined that CLA isomers enhance GJIC in human MCF-7 breast cancer cells and investigated the underlying molecular mechanisms. The CLA isomers significantly enhanced GJIC of MCF-7 cells at 40 μM concentration, whereas CLA inhibited cell growth and induced caspase-dependent apoptosis. CLA increased connexin43 (Cx43) expression both at the transcriptional and translational levels. CLA inhibited nuclear factor-κB (NF-κB) activity and enhanced reactive oxygen species (ROS) generation. No significant difference was observed in the efficacy of c9,t11-CLA and t10,c12-CLA. These results suggest that the anticancer effect of CLA is associated with upregulation of GJIC mediated by enhanced Cx43 expression through inactivation of NF-κB and generation of ROS in MCF-7 cells.

Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1β, and Trastuzumab Application

“…This correlation is a possible reason for the influence of chemotherapeutics which focus on ErbB receptors as their main target but also manipulate gap junctions in conventional breast tumor cells and in tumor stem cells [ 151 , 152 , 153 ]. In particular, it could be shown that the apoptosis activity level of conjugated linoleic acid via stimulation of caspase-3 in MCF-7 breast cancer cells is dependent on gap junction permeability [ 154 ]. Modulators of gap junction permeability derive from pesticides and polychlorinated aromatic compounds, but hormones like estradiol can also induce carcinogenesis in breast epithelial cells with increased ErbB receptor number [ 155 , 156 ].…”

Decreased All-trans Retinoic Acid-Induced Expression of Sodium–Iodide Transporter in Mammary Epithelial Cells Caused by Conjugated Linoleic Acid Isomers

“…Although 24 h treatment with 5−40 μM c9t11-CLA did not affect viability of MCF-7 cells in one study, 31 MCF-7 cell viability was reduced by a 24 h treatment with 40 μM c9t11-CLA and t10c12-CLA in another study. 32 In a further study, both c9t11-CLA and t10c12-CLA decreased MCF-7 cell viability through apoptosis at a concentration of 50 μM.…”

All-trans retinoic acid enhances bystander effect of suicide gene therapy in the treatment of breast cancer

“…To enhance the antitumor activity, we determined whether suicide gene system combined with ATRA could potentiate the destruction of breast cancer. Three connexin proteins have been identified in breast tissues, including Cx43, Cx26 and Cx32 (9). Expression of Cx26 and Cx32 are enhanced during pregnancy and further increased during lactation in normal breast tissues (10).…”

“…Three connexins (Cx43, Cx26 and Cx32) have been shown to be expressed in the human breast tissue in different temporal and spatial patterns. In normal human breast tissues, Cx26 and Cx32 are present in the mammary epithelium, whereas Cx43 is localized mainly to myoepithelial cells (9,10). It was reported that Cxs are often reduced or lost resulting in significantly decreased GJIC in tumor tissues, thus decreased gap junctional communication may be involved in oncogenesis (11).…”