The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells
Wyatt Wollmann 1, Mike L. Goodman 1, Poornima Bhat-Nakshatri 4, 5, Hiromitsu Kishimoto 1, Robert J. Goulet, Jr 1, Sanjana Mehrotra 3, Akira Morimiya 3, Sunil Badve 3 and Harikrishna Nakshatri 1, 2, 4, 5, * 1 Department of Surgery, 2 Department of Biochemistry and Molecular Biology, 3 Department of Pathology and 4 Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA and 5 Walther Cancer Institute, Indianapolis, IN 46208, USA
* To whom correspondence should be addressed at: R4-202 Indiana Cancer Research Institute, 1044 West Walnut Street, Indianapolis, IN 46202, USA. Tel: +1 317 278 2238; Fax: +1 317 274 0396; Email: hnakshat@iupui.edu
Macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor beta superfamily, plays a role in the progression of a number of cancers, including breast, gastric, prostate and colorectal carcinomas. Serum MIC-1 levels are elevated in patients with metastatic prostate, breast and colorectal carcinomas.
In vitro studies have revealed a cell type-specific role for MIC-1 in senescence and apoptosis. MIC-1 activates the survival kinase AKT/PKB in neuronal cells. Depending on the cell type, it activates or represses the MAP kinases ERK1/2. Mechanisms responsible for an increased MIC-1 expression in cancers and the consequences of MIC-1 overexpression, however, are not known. In this study, we show that AKT/PKB directly regulates the expression of MIC-1 in breast cancer cells. Sequences within –88 to +30 of the MIC-1 promoter are required for the AKT-mediated induction of MIC-1. This region of the promoter contains two SP-1 binding sites (SP-1B and SP-1C), which bind to the SP-1 and SP-3 proteins. Mutation of SP-1C but not SP-1B reduced the AKT-mediated activation of MIC-1. MIC-1 increased the basal ERK1 phosphorylation and prolonged the estrogen-stimulated ERK1 phosphorylation in MCF-7 breast cancer cells without altering the phosphorylation status of AKT/PKB. Immunohistochemistry with MIC-1 antibody revealed an MIC-1 expression within the cancer cells of primary breast cancer and in the MCF-7 xenografts. Furthermore, a limited analysis of RNA from primary breast cancers revealed an overexpression of MIC-1 in tumors, compared with normal tissues. These results suggest that AKT/PKB through MIC-1 could regulate the ERK1 activity and the MIC-1 expression levels may serve as a surrogate marker for the AKT activation in tumors.
Abbreviations: CA-AKT, constitutively active AKT; EMSA, electrophoretic mobility shift assay; ER
http://carcin.oxfordjournals.org/math/alpha.gif, estrogen receptor alpha; KD-AKT, kinase dead AKT; MIC-1, macrophage inhibitory cytokine 1; RT–PCR, reverse transcription–polymerase chain reaction
complete article at
http://carcin.oxfordjournals.org/cgi.../full/26/5/900
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