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Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK–RhoA signaling pathway

Oncogene volume 29, pages 1293–1302 (2010)Cite this article

Abstract

An elevated level of macrophage inhibitory cytokine-1 (MIC-1) is reported in the sera of patients with metastatic prostate cancer compared with that of benign diseases and healthy adults. We investigated the mechanistic role of MIC-1 overexpression in the metastasis of prostate cancer cells. Our study showed a progressive increase in secretory MIC-1 production correlated with the increase in the metastatic potential of PC-3 and LNPCa prostate cancer metastatic variants. Further, the in vitro studies using ‘loss-’ and ‘gain’-of-function approaches showed that ectopic overexpression of MIC-1 (PC-3-MIC-1) and forced downregulation of MIC-1(PC-3M-siMIC-1) enhanced and reduced the motility and invasiveness of these cells, respectively. Supporting our in vitro observations, all the mice orthotopically implanted with PC-3-MIC-1 cells developed metastasis compared with none in the PC-3-vector group. Our results showed that MIC-1 overexpression was associated with apparent changes in actin organization. In addition, an enhanced phosphorylation of focal adhesion kinase (FAK) and guanosine-5′-triphosphate (GTP)-bound RhoA was also seen; however, no significant change was observed in total FAK and RhoA levels in the PC-3-MIC-1 cells. Altogether, our findings show that MIC-1 has a role in prostate cancer metastasis, in part, by promoting the motility of these cells. Activation of the FAK–RhoA signaling pathway is involved in MIC-1-mediated actin reorganization, and thus, leads to an increase in the motility of prostate cancer cells.

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Acknowledgements

This study was supported, in part, by grants from the Department of Defense (PC040502 and PC074289). We thank Dr Ajay P Singh for reading the paper and for his valuable suggestions. We also thank Erik Moore for his technical assistance and Kristi LW Berger for editing the paper. We also acknowledge the NCI Cancer Center Support Grant (P30 CA36727) to UNMC.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    S Senapati, S Rachagani, K Chaudhary & S K Batra

  2. Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    S L Johansson & R K Singh

  3. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    S L Johansson, R K Singh & S K Batra

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  1. S Senapati
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  2. S Rachagani
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  5. R K Singh
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  6. S K Batra
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Correspondence to S K Batra.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Senapati, S., Rachagani, S., Chaudhary, K. et al. Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK–RhoA signaling pathway. Oncogene 29, 1293–1302 (2010). https://doi.org/10.1038/onc.2009.420

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