Abstract
Dysregulated activation of the WNT/β-catenin signaling pathway is essential for the initiation and development of various cancers. E7386, a small-molecule compound, attenuates WNT signaling by blocking the interaction between β-catenin and CREB-binding protein (CBP); hence, it is regarded as a therapeutic candidate for cancers with activated WNT signaling. In the present study, we evaluated the biological characteristics associated with E7386 sensitivity by using a panel of patient-derived colon cancer spheroids. An integrative approach that combined E7386 sensitivity and gene expression profiles revealed that the resistance of the cancer spheroids to E7386 was associated with the activation of the NF-κB pathway. NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.
Keywords:
E7386; NF-κB; Patient-derived spheroids; WNT signaling Pathway.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / drug therapy
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology
-
CREB-Binding Protein / genetics*
-
CREB-Binding Protein / metabolism
-
Cell Cycle Checkpoints / drug effects
-
Cell Cycle Checkpoints / genetics
-
Cell Proliferation / drug effects
-
Colonic Neoplasms / drug therapy
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / metabolism
-
Colonic Neoplasms / pathology
-
Drug Synergism
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Liver Neoplasms / drug therapy
-
Liver Neoplasms / genetics
-
Liver Neoplasms / metabolism
-
Liver Neoplasms / pathology
-
NF-kappa B / antagonists & inhibitors
-
NF-kappa B / genetics*
-
NF-kappa B / metabolism
-
Phenylenediamines / pharmacology*
-
Primary Cell Culture
-
Pyrazines / pharmacology*
-
Spheroids, Cellular / drug effects*
-
Spheroids, Cellular / metabolism
-
Spheroids, Cellular / pathology
-
Triazines / pharmacology*
-
Wnt Signaling Pathway
-
beta Catenin / genetics*
-
beta Catenin / metabolism
Substances
-
4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine
-
CTNNB1 protein, human
-
NF-kappa B
-
Phenylenediamines
-
Pyrazines
-
Triazines
-
beta Catenin
-
CREB-Binding Protein
-
CREBBP protein, human
-
E-7386