Adiponectin Modulates the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway and Attenuates Mammary Tumorigenesis of MDA-MB-231 Cells in Nude Mice

Abstract

Adiponectin is an adipokine that has pleiotropic beneficial roles in systemic insulin resistance and inflammation. Several recent clinical studies suggest that low serum levels of adiponectin are associated with increased risks of breast cancer. Here, we investigated the direct effects of adiponectin on breast cancer development in vitro and in vivo. Our results showed that adiponectin significantly attenuated the proliferations of two typical human breast cancer cells, MDA-MB-231 and T47D, in a cell type-specific manner. Further analysis revealed that adiponectin could induce apoptosis and arrest the cell cycle progression at G 0 -G 1 phase in MDA-MB-231 cells. Prolonged treatment with adiponectin in this cell line blocked serum-induced phosphorylation of Akt and glycogen synthase kinase-3B (GSK-3B), suppressed intracellular accumulation of B-catenin and its nuclear activities, and consequently reduced expression of cyclin D1. Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3B inhibitor lithium chloride. These results suggest that the inhibitory role of adiponectin on MDA-MB-231 cell growth might be attributed to its suppressive effects on the GSK-3B/B-catenin signaling pathway. Furthermore, our in vivo study showed that both supplementation of recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice. Taken together, these data support the role of adiponectin as a negative regulator of breast cancer development and also suggest that adiponectin might represent a novel therapeutic target for this disease.

Effects of adiponectin on breast cancer cell growth and signaling

“…This was suggested by the increase in cleaved caspase-8 and cleaved PARP in these cells. Other reports have found that apoptosis is involved in growth inhibition by Acrp30 by the use of TUNEL or annexin V assays (Kang et al, 2005;Dieudonne et al, 2006;Wang et al, 2006). We have extended those earlier observations by identifying increased cleavage of caspase-8 and PARP following treatment with Acrp30.…”

“…Very little work has been done in this area with only one previous mention that gAcrp30 did not affect MDA-MB-231 cells growth but the data were not shown (Wang et al, 2006). In our hands the addition of gAcrp30 to MDA-MB-231 cells resulted in fewer cells after 48 hours but the reduction was not statistically significant.…”

“…In vitro assays have indicated that the addition of Acrp30 to the human MDA-MB-231 breast cancer cell line-induced growth arrest and promoted apoptosis (Kang et al, 2005;Wang et al, 2006). Addition of Acrp30 also blocked phosphorylation of Akt and reduced the expression of cyclin D1 (Wang et al, 2006).…”

Hormonal regulation of immune modulators in human breast tissue

“…In vitro studies have demonstrated that adiponectin induced apoptosis and inhibited migration and invasion of breast cancer cells (152,153). Furthermore, adiponectin suppressed the growth of the cancer in experimental breast cancer xenografts (146). Both AdipoR1 and AdipoR2 were detected in breast cancer tissue (154)(155)(156) and in breast cancer cell lines (157).…”

“…Several studies have shown the negative effect of adiponectin on the proliferation of several cancer cell lines (144,146). Epidemiological studies, using serum adiponectin level as a measure of tissue exposure, suggested that adiponectin was a protective factor against breast cancer (147)(148)(149)(150)(151).…”