title: 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: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Hubei Cancer Hospital, Wuhan 430079, China.
authors: Qiongrong
authors: Q
authors: Chen
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Shumei
authors: S
authors: Song
authors: Hubei Cancer Hospital, Wuhan 430079, China.
authors: Shaozhong
authors: S
authors: Wei
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Bin
authors: B
authors: Liu
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Soichiro
authors: S
authors: Honjo
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Ailing
authors: A
authors: Scott
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jiankang
authors: J
authors: Jin
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Lang
authors: L
authors: Ma
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Haitao
authors: H
authors: Zhu
authors: Departments of Biochemistry & Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Heath D
authors: HD
authors: Skinner
authors: Departments of Biochemistry & Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Randy L
authors: RL
authors: Johnson
authors: Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jaffer A
authors: JA
authors: Ajani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014157:Transcription Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D013449:Sulfonamides; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D005472:Fluorouracil; C528561:navitoclax
keywords: 5-fluorouracil; ABT-263; cancer stem cells; esophageal cancer; stemness pathways