title: Raf kinase inhibitor protein (RKIP) blocks signal transducer and activator of transcription 3 (STAT3) activation in breast and prostate cancer.
abstract: Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding-protein (PEBP) family that modulates the action of many kinases involved in cellular growth, apoptosis, epithelial to mesenchymal transition, motility, invasion and metastasis. Previously, we described an inverse association between RKIP and signal transducers and activators of transcription 3 (STAT3) expression in gastric adenocarcinoma patients. In this study, we elucidated the mechanism by which RKIP regulates STAT3 activity in breast and prostate cancer cell lines. RKIP over expression inhibited c-Src auto-phosphorylation and activation, as well as IL-6-, JAK1 and 2-, and activated Raf-mediated STAT3 tyrosine and serine phosphorylation and subsequent activation. In MDA-231 breast cancer cells that stably over express RKIP, IL-6 treatment blocked STAT3 phosphorylation and transcriptional activation. Conversely, in RKIP knockdown MDA-231 cells: STAT3 phosphorylation and activation increased in comparison to parental MDA-231 cells. RKIP over expression resulted in constitutive physical interaction with STAT3 and blocked c-Src and STAT3 association. The treatment of DU145 prostate, but not PC3 prostate or MDA-231 breast, cancer cell lines with ENMD-1198 or MKC-1 dramatically increased expression of RKIP. Overexpression of RKIP sensitized PC3 and MDA-231 cells to MTI-induced apoptosis. Moreover, MTI treatment resulted in a decrease in Src-mediated STAT3 tyrosine phosphorylation and activation, an effect that was significantly enhanced by RKIP over expression. In stable RKIP over expressing MDA-231 cells, tumor xenograft growth induced by activated STAT3 is inhibited. RKIP synergizes with MTIs to induce apoptosis and inhibit STAT3 activation of breast and prostate cancer cells. RKIP plays a critical role in opposing the effects of pro-oncogenic STAT3 activation.
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Saad
authors.initials: S
authors.lastname: Yousuf
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America; Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: MeiLi
authors.initials: M
authors.lastname: Duan
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Moen
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Cross-Knorr
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Kate
authors.initials: K
authors.lastname: Brilliant
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.affiliation: Kolltan Pharmaceuticals, Inc., New Haven, Connecticut, United States of America.
authors.forename: Theresa
authors.initials: T
authors.lastname: LaValle
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Kam C
authors.initials: KC
authors.lastname: Yeung
authors.affiliation: Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Surgical Research, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Eugene
authors.initials: E
authors.lastname: Chin
authors.affiliation: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Devasis
authors.initials: D
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D049488:Phosphatidylethanolamine Binding Protein / Q000096:biosynthesis / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D004963:Estrenes; D015850:Interleukin-6; D053613:Janus Kinase 1; D049488:Phosphatidylethanolamine Binding Protein; D050796:STAT3 Transcription Factor; D050257:Tubulin Modulators; D000093242:Interleukin-6 Inhibitors; C530263:2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide