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, Santanu Bhattacharya, S. Debnath, S. Roy, Lisa Allyn Boardman, Thomas Christopher Smyrk, Julian R Molina, S. Chakrabarti, S. Chowdhury, Debabrata Mukhopadhyay, S. Roychoudhury

Research output: Contribution to journalArticle

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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

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Ephrin-B2
Epithelial-Mesenchymal Transition
DNA Damage
Colorectal Neoplasms
p53 Genes
Neoplasms
MAP Kinase Signaling System
Mutant Proteins
Computational Biology
Drug Resistance
Nude Mice
Fluorouracil
Carcinogenesis
Up-Regulation
Cell Line
Mutation
DNA
Incidence
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. / Alam, S. K.; Yadav, V. K.; Bajaj, S.; Datta, A.; Dutta, S. K.; Bhattacharyya, M.; Bhattacharya, Santanu; Debnath, S.; Roy, S.; Boardman, Lisa Allyn; Smyrk, Thomas Christopher; Molina, Julian R; Chakrabarti, S.; Chowdhury, S.; Mukhopadhyay, Debabrata; Roychoudhury, S.

In: Cell Death and Differentiation, Vol. 23, No. 4, 01.04.2016, p. 707-722.

Research output: Contribution to journalArticle

Alam, SK, Yadav, VK, Bajaj, S, Datta, A, Dutta, SK, Bhattacharyya, M, Bhattacharya, S, Debnath, S, Roy, S, Boardman, LA, Smyrk, TC, Molina, JR, Chakrabarti, S, Chowdhury, S, Mukhopadhyay, D & Roychoudhury, S 2016, 'DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53', Cell Death and Differentiation, vol. 23, no. 4, pp. 707-722. https://doi.org/10.1038/cdd.2015.133
Alam, S. K. ; Yadav, V. K. ; Bajaj, S. ; Datta, A. ; Dutta, S. K. ; Bhattacharyya, M. ; Bhattacharya, Santanu ; Debnath, S. ; Roy, S. ; Boardman, Lisa Allyn ; Smyrk, Thomas Christopher ; Molina, Julian R ; Chakrabarti, S. ; Chowdhury, S. ; Mukhopadhyay, Debabrata ; Roychoudhury, S. / DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. In: Cell Death and Differentiation. 2016 ; Vol. 23, No. 4. pp. 707-722.
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AU - Roy, S.

AU - Boardman, Lisa Allyn

AU - Smyrk, Thomas Christopher

AU - Molina, Julian R

AU - Chakrabarti, S.

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AU - Mukhopadhyay, Debabrata

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