title: Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity.
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.
authors.affiliation: Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Hae Sook
authors.initials: HS
authors.lastname: Noh
authors.affiliation: Biomedical Research Institute of Gyeongsang National Hospital, Gyeongsang National University, JinJu, Republic of Korea.
authors.forename: Young-Sool
authors.initials: YS
authors.lastname: Hah
authors.affiliation: Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Ha
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Sahib
authors.initials: S
authors.lastname: Zada
authors.affiliation: Department of Internal Medicine, Yonsei Cancer Center, Songang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Anatomy and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Oral and Maxillofacial Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: June-Ho
authors.initials: JH
authors.lastname: Byun
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Jong Ryeal
authors.initials: JR
authors.lastname: Hahm
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Shin
authors.affiliation: Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.
authors.forename: Deok Ryong
authors.initials: DR
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D012333:RNA, Messenger; D051881:Receptor, Notch1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: EMT; ERK; Notch1; RKIP; metastasis