ABT-263 induces apoptosis and synergizes with chemotherapy by targeting stemness pathways in esophageal cancer.

Oncotarget
Qiongrong ChenJaffer A Ajani

Abstract

Activation of cancer stem cell signaling is central to acquired resistance to therapy in esophageal cancer (EC). ABT-263, a potent Bcl-2 family inhibitor, is active against many tumor types. However, effect of ABT-263 on EC cells and their resistant counterparts are unknown. Here we report that ABT-263 inhibited cell proliferation and induced apoptosis in human EC cells and their chemo-resistant counterparts. The combination of ABT-263 with 5-FU had synergistic lethal effects and amplified apoptosis that does not depend fully on its inhibition of BCL-2 family proteins in EC cells. To further explore the novel mechanisms of ABT-263, proteomic array (RPPAs) were performed and gene set enriched analysis demonstrated that ABT-263 suppresses the expression of many oncogenes including genes that govern stemness pathways. Immunoblotting and immunofluorescence further confirmed reduction in protein expression and transcription in Wnt/β-catenin and YAP/SOX9 axes. Furthermore, ABT263 strongly suppresses cancer stem cell properties in EC cells and the combination of ABT-263 and 5-FU significantly reduced tumor growth in vivo and suppresses the expression of stemness genes. Thus, our findings demonstrated a novel mechanism of ABT-263 antit...Continue Reading

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Citations

Apr 9, 2017·Journal of Gastroenterology·Atsushi ShiozakiEigo Otsuji
Jul 23, 2020·Journal of Cellular Physiology·Emel RothzergJiake Xu
Feb 20, 2018·Experimental and Therapeutic Medicine·Yingcai HongZhenglei Xu
Dec 5, 2019·Nature Metabolism·Ana GuerreroJesús Gil
Sep 28, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhenqian WuJun Yan
Mar 17, 2020·Aging Cell·Ana GuerreroJesús Gil
Mar 6, 2021·Frontiers in Oncology·Plabon Kumar DasAlfred K Lam
Sep 7, 2016·Mayo Clinic Proceedings·Elena ElimovaJaffer A Ajani
Jan 1, 2020·Exploration of Targeted Anti-tumor Therapy·Peiyi ZhangGuangrong Zheng
Aug 7, 2021·Cellular Signalling·Chorlada PaiboonrungruangXiaoxin Chen

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Datasets Mentioned

BETA
ABT-263

Methods Mentioned

BETA
xenograft
flow-cytometry
flow cytometry
transfection
xenografts
fluorescence-activated cell sorting

Software Mentioned

CellQuest PRO
SPSS
GSEA
Image J

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