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

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 antitumor effect in EC and indicating that combination of ABT-263 with cytotoxic drugs is worthy of pursuit in patients with EC.

• Authors: Qiongrong Chen, Shumei Song, Shaozhong Wei, Bin Liu, Soichiro Honjo, Ailing Scott, Jiankang Jin, Lang Ma, Haitao Zhu, Heath D Skinner, Randy L Johnson, Jaffer A Ajani
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 25883-96 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26317542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Aniline Compounds
• Antineoplastic Agents
• Phosphoproteins
• SOX9 Transcription Factor
• SOX9 protein, human
• Sulfonamides
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Fluorouracil
• navitoclax

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Aniline Compounds (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, genetics)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Esophageal Neoplasms (drug therapy, genetics, metabolism)
• Fluorouracil (administration & dosage, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice, Nude
• Microscopy, Confocal
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phosphoproteins (genetics, metabolism)
• Proteomics (methods)
• SOX9 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Sulfonamides (administration & dosage, pharmacology)
• Transcription Factors
• Wnt Signaling Pathway (drug effects, genetics)
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins