DNA damage-induced ephrin-B2 reverse signalling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
DNA damage-induced ephrin-B2 reverse signalling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53
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| Creator |
Alam, SK
Yadav, VK Bajaj, S Datta, A Datta, SK Bhattacharyya, M Bhattacharya, S Debnath, S Roy, S Boardman, LA Smyrk, TC Molina, JR Chakrabarti, S Chowdhury, S Mukhopadhyay, D Roychoudhury, S |
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
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
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| Publisher |
Nature Publishing Group
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| Date |
2016
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2500/1/Cell_Death_and_Differentiation_(2016)_23%2C_707%E2%80%93722.pdf
Alam, SK and Yadav, VK and Bajaj, S and Datta, A and Datta, SK and Bhattacharyya, M and Bhattacharya, S and Debnath, S and Roy, S and Boardman, LA and Smyrk, TC and Molina, JR and Chakrabarti, S and Chowdhury, S and Mukhopadhyay, D and Roychoudhury, S (2016) DNA damage-induced ephrin-B2 reverse signalling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. Cell Death and Differentiation, 23. pp. 707-722. |
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| Relation |
http://dx.doi.org/10.1038/cdd.2015.133
http://www.eprints.iicb.res.in/2500/ |
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