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

Abstract

// Qiongrong Chen 1, 3 , Shumei Song 1 , Shaozhong Wei 3 , Bin Liu 4 , Soichiro Honjo 1 , Ailing Scott 1 , Jiankang Jin 1 , Lang Ma 1 , Haitao Zhu 1 , Heath D. Skinner 2 , Randy L. Johnson 2 , Jaffer A. Ajani 1 1 Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 2 Departments of Biochemistry & Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 3 Hubei Cancer Hospital, Wuhan 430079, China 4 Departments of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Correspondence to: Shumei Song, e-mail: ssong@mdanderson.org Jaffer A. Ajani, e-mail: jajani@mdanderson.org Keywords: esophageal cancer, stemness pathways, cancer stem cells, ABT-263, 5-fluorouracil Received: March 12, 2015      Accepted: July 06, 2015      Published: July 17, 2015 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.