Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells

• Published in: Carcinogenesis (New York) 2008-04, Vol.29 (4), p.704-712
• Main Authors: Kim, Kwang-Kyu, Lee, Jung Joon, Yang, Young, You, Kwan-Hee, Lee, Jeong-Hyung
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Cytokines - physiology; DNA Primers; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15; Gynecology. Andrology. Obstetrics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Mammary gland diseases; Medical sciences; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - genetics; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcriptional Activation; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgn031

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 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-1α 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.