1. Mel-18 Negatively Regulates INK4a/ARF-Independent Cell Cycle Progression via Akt Inactivation in Breast Cancer
- Author
-
Kiseok Jang, Hyun-Jun Kim, Mi-Yun Oh, Gu Kong, Dong-Hui Shin, Yong-Seok Kim, and Jeong-Yeon Lee
- Subjects
Cancer Research ,Blotting, Western ,Down-Regulation ,Fluorescent Antibody Technique ,Breast Neoplasms ,Cyclin D1 ,Cancer stem cell ,Cyclin-dependent kinase ,Cell Line, Tumor ,hemic and lymphatic diseases ,Tumor Suppressor Protein p14ARF ,Humans ,Phosphorylation ,neoplasms ,Protein kinase B ,Cyclin-Dependent Kinase Inhibitor p16 ,Polycomb Repressive Complex 1 ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Kinase ,Akt/PKB signaling pathway ,Cell Cycle ,Cyclin-dependent kinase 2 ,Cell biology ,Carcinoma, Ductal ,DNA-Binding Proteins ,Repressor Proteins ,carbohydrates (lipids) ,Oncology ,biology.protein ,Proto-Oncogene Proteins c-akt - Abstract
Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G1 arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G1-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27Kip1 phosphorylation at Thr157, but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser473 was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27Kip1 was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3β phosphorylation, β-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18→Akt→G1 phase regulators. [Cancer Res 2008;68(11):4201–9]
- Published
- 2008