Raf kinase inhibitor protein (RKIP) blocks signal transducer and activator of transcription 3 (STAT3) activation in breast and prostate cancer
Authors: Kam C Yeung
Devasis Chatterjee
Saad Yousuf
Erika L Moen
Theresa LaValle
Sam Cross-Knorr
Fahd Al-Mulla
Benjamin Bonavida
Eugene Chin
MeiLi Duan
Kate Brilliant
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: RKIP; STAT3; cancer cell lines; apoptosis; c-Src
Affiliations: Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America., 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., Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America., Kolltan Pharmaceuticals, Inc., New Haven, Connecticut, United States of America., Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Toledo, Ohio, United States of America., Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait., Department of Surgical Research, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.

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. 

Retracted: Yes

PubPeer comments:
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 Some additional concerns about Figure 4A: Some pY705 STAT3 lanes in the left panel appear to look similar to lanes in the right panel - shown with red and blue boxes. In addition, in the left panel, lanes 3 and 4 appear to look similar to lanes 7 and 8. Shown with purple boxes. ![file] , 
 Another concern, about Figure 4B. In the IB: HA panel, lanes 1 and 3 appear to look unexpectedly similar. Shown with orange boxes. ![file] , 
 ![file] , 
 Retracted [10 June 2021] . --------------------------- Following the publication of this article [1], concerns were raised regarding results presented in Figs 1, 2, and 4. Specifically, Vertical irregularities suggestive of splice lines were detected in the following panels: - Fig 1D, RKIP panel, between lanes 2 and 3. - Fig 2A DU145 RKIP panel, between lanes 1 and 2, as well as between lanes 2 and 3. - Fig 2A PC3 RKIP panel, between lanes 1 and 2, as well as between lanes 2 and 3. In Fig 2D, the PC3 PARP panel appears similar to the first two lanes of the right (DU145) panel, despite representing results obtained from different cell lines. In Fig 4A, the following similarities were detected between lanes presented in the middle panel and lanes presented in the right panel: - The first two lanes of the middle pY705 STAT3 panel appear similar to the first two lanes of the right pY705 STAT 3 panel. However, the corresponding Actin panel results for these lanes do not appear to match. - Lanes 3 and 4 in the middle panel appear similar to lanes 7 and 8 in the middle panel respectively, despite being used to represent different experimental conditions. - The last lane of the middle pY705 STAT3 panel appears similar to the last lane of the right pY705 STAT3 panel, despite being used to represent different experimental conditions. The authors have not provided the original images underlying the panels of concern. In light of the concerns affecting multiple figure panels that question the integrity of the data, the PLOS ONE Editors retract this article. ELM agreed with the retraction and apologises for the issues with the published article. BB did not agree with the retraction. SY, MD, SC-K, KB, TL, KCY, FA-M, EC, and DC either did not respond directly or could not be reached. ,