Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells
- Authors
- Kim, Kwang-Kyu; Lee, Jung Joon; Yang, Young; You, Kwan-Hee; Lee, Jeong-Hyung
- Issue Date
- Apr-2008
- Publisher
- OXFORD UNIV PRESS
- Citation
- CARCINOGENESIS, v.29, no.4, pp 704 - 712
- Pages
- 9
- Journal Title
- CARCINOGENESIS
- Volume
- 29
- Number
- 4
- Start Page
- 704
- End Page
- 712
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/14294
- DOI
- 10.1093/carcin/bgn031
- ISSN
- 0143-3334
1460-2180
- Abstract
- Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-beta 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 small-interfering RNA-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 alpha protein and the expression of its target genes, including vascular endothelial growth factor, 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.
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