PMID- 18258606
OWN - NLM
STAT- MEDLINE
DCOM- 20080428
LR  - 20141120
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 29
IP  - 4
DP  - 2008 Apr
TI  - Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the 
      transactivation of ErbB2 in human breast and gastric cancer cells.
PG  - 704-12
LID - 10.1093/carcin/bgn031 [doi]
AB  - 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-1alpha 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.
FAU - Kim, Kwang-Kyu
AU  - Kim KK
AD  - Molecular Cancer Research Center, Korea Research Institute of Bioscience and 
      Biotechnology, Daejeon, Republic of Korea.
FAU - Lee, Jung Joon
AU  - Lee JJ
FAU - Yang, Young
AU  - Yang Y
FAU - You, Kwan-Hee
AU  - You KH
FAU - Lee, Jeong-Hyung
AU  - Lee JH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080206
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Cytokines)
RN  - 0 (DNA Primers)
RN  - 0 (GDF15 protein, human)
RN  - 0 (Growth Differentiation Factor 15)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Breast Neoplasms/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cytokines/*physiology
MH  - DNA Primers
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Growth Differentiation Factor 15
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinase Kinases/*genetics
MH  - Neoplasm Invasiveness
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA Interference
MH  - Receptor, ErbB-2/*genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stomach Neoplasms/genetics/pathology
MH  - Transcriptional Activation
EDAT- 2008/02/09 09:00
MHDA- 2008/04/29 09:00
CRDT- 2008/02/09 09:00
PHST- 2008/02/09 09:00 [pubmed]
PHST- 2008/04/29 09:00 [medline]
PHST- 2008/02/09 09:00 [entrez]
AID - bgn031 [pii]
AID - 10.1093/carcin/bgn031 [doi]
PST - ppublish
SO  - Carcinogenesis. 2008 Apr;29(4):704-12. doi: 10.1093/carcin/bgn031. Epub 2008 Feb 
      6.