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.
Highlights
Tumor metastasis is a multistep process that begins with the separation of cancer cells from the primary tumor followed by local invasion, intravasation into the bloodstream, extravasation, and final colonization at distant organs
We show that Raf kinase inhibitory protein (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
Compared to control cells transfected with pLK 0.1-GFP shRNA, expression levels of RKIP were not affected in Notch1-knocking down cells (Figure 1E), suggesting that RKIP is an upstream component of Notch1 signaling in these cancer cells
Summary
Tumor metastasis is a multistep process that begins with the separation of cancer cells from the primary tumor followed by local invasion, intravasation into the bloodstream, extravasation, and final colonization at distant organs. Metastasis is the major cause of cancer-associated death and poor prognosis in humans. Each step of tumor metastasis requires specific cell-cell interactions and many different signaling pathways [1, 2]. Before the metastatic progression of a tumor begins, a cancer cell commits to a transition from an epithelial to a mesenchymal phenotype; this process is called the epithelial-mesenchymal transition (EMT). It allows cancer cells to be highly migratory during metastasis [3, 4]. The EMT process coincides with the simultaneous loss of epithelial markers, such as E-cadherin, and the acquisition of mesenchymal markers, such as N-cadherin and vimentin, by activating the transcriptional factors, Snail, Slug, Twist, and ZEB1/ZEB2 [5, 6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
