Prevention of epithelial to mesenchymal transition in colorectal carcinoma by regulation of the E-cadherin-β-catenin-vinculin axis
Authors: Sudip K Ghosh
Y Rajesh
Payel Banik
Ipsita Pal
Mahitosh Mandal
Rashmi Bharti
Luni Emdad
Deboki Naskar
Subhas Chandra Kundu
Goutam Dey
Paul B Fisher
Swadesh K Das
Sandipan Chakraborty
Kaushik Kumar Dey
Journal: Cancer Letters (2019)
Discipline: CLINICAL MEDICINE
Keywords: Akt; E-Cadherin; EMT; NF-κB; TGF-β
Affiliations: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India; Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, NY, USA., School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India., St. Jude Children's Research Hospital, Memphis, TN, USA., Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India., Interfaith Medical Center, Brooklyn, NY, USA., Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA., Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India; I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, AvePark - 4805-017 Barco, Guimaraes, Portugal., Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, and VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA. Electronic address: ., School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India. Electronic address: .

Abstract:  Epithelial to mesenchymal transition (EMT) is compulsory for metastatic dissemination and is stimulated by TGF-β. Although targeting EMT has significant therapeutic potential, very few pharmacological agents have been shown to exert anti-metastatic effects. BI-69A11, a competitive Akt inhibitor, displays anti-tumor activity toward melanoma and colon carcinoma. This study provides molecular and biochemical insights into the effects of BI-69A11 on EMT in colon carcinoma cells in vitro and in vivo. BI-69A11 inhibited metastasis-associated cellular migration, invasion and adhesion by inhibiting the Akt-β-catenin pathway. The underlying mechanism of BI-69A11-mediated inhibition of EMT included suppression of nuclear transport of β-catenin and diminished phosphorylation of β-catenin, which was accompanied by enhanced E-cadherin-β-catenin complex formation at the plasma membrane. Additionally, BI-69A11 caused increased accumulation of vinculin in the plasma membrane, which fortified focal adhesion junctions leading to inhibition of metastasis. BI-69A11 downregulated activation of the TGF-β-induced non-canonical Akt/NF-κB pathway and blocked TGF-β-induced enhanced expression of Snail causing restoration of E-cadherin. Overall, this study enhances our understanding of the molecular mechanism of BI-69A11-induced reversal of EMT in colorectal carcinoma cells in vitro, in vivo and in TGF-β-induced model systems. 

Retracted: No

PubPeer comments:
 There is an unexpected similarity between the E-cadherin BI-69A11 panel in Figure 5F and the Vinculin BI-69A11 panel in Figure 6F. The similarities between these 2 figures (marked with green boxes) is much more than one would expect of incubations with two different antibodies. Could the authors please explain? ![file] , 
 #1 Thanks, Pubpeer for reaching out and letting us inform a prior mistake in our figure no 6F. We apologize for this unintentional mistake. This must have happened during the rearrangement of the figures for the revision. We are going to rectify this error and going to replace the image. We are also going to write the editor and will soon publish an erratum. , 
 Thank you for your comment. I am forwarding your comment to Dr. Mahitosh Mandel (Co-contributing author, in whose laboratory these studies were conducted by Dr. Ipsita Pal). P. Fisher , 
 Thank you, Dr. Fisher and Dr. Mandal, for checking in and correcting the mistake. Much appreciated. , 
 Drs. Fisher and Mandal: Might you provide an update to this correction? Also, I have noted some apparent image issues for another paper on which you are co-authors: https: pubpeer.com publications 6C1907821FB586C71973BA71D1A35B Perhaps you can address the concerns on that thread. Thank you. , 
 It seems to me that the BI-69A11 E-cadherin image is also very similar to the two marked out in green, but enlarged and slightly rotated. , 
 #6 I believe you are correct. , 
 #6 Yes, there are overlapping areas between the left and the right panels, but that is because they are zoomed-in versions of the same. As stated in the legend, pictures were taken at 20X and 40x magnification. So I did not mark this as a duplication. , 
 And more issues with blots: ![file] , 
 #9 Is that necessarily a problem, though? If the NF-kB band in 7E came from the same gel as the bands in 7C - being displayed separately for the comparison of whole, nuclear and cytoplasmic lysates - it would be reasonable to repeat the beta-Actin band for clarity. , 
 2020 corrigendum. https: www.sciencedirect.com science article pii S0304383520303013?via%3Dihub The authors regret that an incorrect set of immunohistochemistry stained sections were used in preparing Fig. 6F. Tumor section slides were re-stained with the appropriate antibodies and a corrected Fig. 6F is now provided. This corrected figure does not alter the conclusions of our study or the hypothesis we proposed. The figure legend remains the same for this corrected figure. The authors would like to apologise for any inconvenience caused. ,