DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

S. K. Alam, V. K. Yadav, S. Bajaj, A. Datta, S. K. Dutta, M. Bhattacharyya, S. Bhattacharya, S. Debnath, S. Roy, L. A. Boardman, T. C. Smyrk, J. R. Molina, S. Chakrabarti, S. Chowdhury, D. Mukhopadhyay, S. Roychoudhury

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42 Scopus citations

Abstract

Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors.

Original languageEnglish (US)
Pages (from-to)707-722
Number of pages16
JournalCell Death and Differentiation
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2016

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr Santu Bandyopadhyay (CSIR-Indian Institute of Chemical Biology, India) for his valuable suggestion during FACS analysis. We are also grateful to Sneha Vivekanandan (Mayo Clinic, USA) and Julie S Lau (Mayo Clinic, USA) for their valuable help in 3D cell culture assay and nude mice experiment, respectively. We are grateful to Dr Sumana Bhattacharjya for her assistance in manuscript editing. We also acknowledge Mayo Clinic Histology Core Facility for their assistance in this work. This work was supported by CSIR-Mayo Clinic Collaboration for Innovation and Translational Research Grant CMPP-08 to S Roychoudhury and MLP-1203 to S Chowdhury; Council of Scientific and Industrial Research (CSIR) Grant IAP-001 to S Roychoudhury, and BSC-0121 to S Chakrabarti; Department of Biotechnology (DBT) Grant BT/01/COE/05/04 to S Roychoudhury. This work was also partly supported by NIH Grant CA150190 to D Mukhopadhyay and Mayo Clinic Foundation. SKA, AD, and MB are supported by predoctoral fellowship from the Council of Scientific and Industrial Research (New Delhi, India). S Chowdhury is a Senior Research Fellows of the Wellcome Trust/ Department of Biotechnology India Alliance (500127/Z/09/Z). VKY acknowledges postdoctoral fellowship from Wellcome Trust/Department of Biotechnology India Alliance (500127/Z/09/Z).

Publisher Copyright:
© 2016 Macmillan Publishers Limited All rights reserved.

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