Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity

Hae Sook Noh, Young Sool Hah, Ji Hye Ha, Min Young Kang, Sahib Zada, Sun Young Rha, Sang Soo Kang, Hyun Joon Kim, Jae-Yong Park, June Ho Byun, Jong Ryeal Hahm, Jeong Kyu Shin, Sang Ho Jeong, Young Joon Lee, Deok Ryong Kim

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and a prognostic marker in cancers. However, how RKIP acts as a suppressor during metastasis is not fully understood. Here, we show that RKIP activity in cervical and stomach cancer is inversely correlated with endogenous levels of the Notch1 intracellular domain (NICD), which stimulates the epithelial to mesenchymal transition (EMT) and metastasis. The levels of RKIP were significantly decreased in tumor tissues compared to normal tissues, whereas NICD levels were increased. Overexpression of RKIP in several cell lines resulted in a dramatic decrease of NICD and subsequent inhibition of several mesenchymal markers, such as vimentin, N-cadherin, and Snail. In contrast, knockdown of RKIP exhibited opposite results both in vitro and in vivo using mouse models. Nevertheless, knockdown of Notch1 in cancer cells had no effect on the expression of RKIP, suggesting that RKIP is likely an upstream regulator of the Notch1 pathway. We also found that RKIP directly interacts with Notch1 but has no influence on the intracellular level of the γ-secretase complex that is necessary for Notch1 activation. These data suggest that RKIP plays a distinct role in activation of Notch1 during EMT and metastasis, providing a new target for cancer treatment.

Original languageEnglish
Pages (from-to)4632-4646
Number of pages15
JournalOncotarget
Volume7
Issue number4
DOIs
Publication statusPublished - 2016 Jan 1

Keywords

  • EMT
  • ERK
  • Metastasis
  • Notch1
  • RKIP

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Noh, H. S., Hah, Y. S., Ha, J. H., Kang, M. Y., Zada, S., Rha, S. Y., Kang, S. S., Kim, H. J., Park, J-Y., Byun, J. H., Hahm, J. R., Shin, J. K., Jeong, S. H., Lee, Y. J., & Kim, D. R. (2016). Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity. Oncotarget, 7(4), 4632-4646. https://doi.org/10.18632/oncotarget.6728