Carcinogenesis Advance Access published online on February 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn031
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Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells
1 Molecular Cancer Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea
2 Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea
3 Department of Biology, Chungnam National University, Daejeon, Republic of Korea
4 Department of Biochemistry and Research Institute of Life Science, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea
* Correspondence to: Jeong-Hyung Lee, Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea. Tel:82-33-250-8519; Fax:82-33-242-0459; E-mail: jhlee36{at}kangwon.ac.kr
Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-β superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2, and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the siRNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1
(HIF-1) protein and the expression of its target genes, including vascular endothelial growth factor (VEGF), via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.
Key Words: MIC-1 • ErbB2 • Akt • ERK-1/2 • HIF
Received August 15, 2007; revised January 6, 2008; accepted January 26, 2008.