Oncotarget

Research Papers:

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

Qiongrong Chen, Shumei Song _, Shaozhong Wei, Bin Liu, Soichiro Honjo, Ailing Scott, Jiankang Jin, Lang Ma, Haitao Zhu, Heath D. Skinner, Randy L. Johnson and Jaffer A. Ajani

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Oncotarget. 2015; 6:25883-25896. https://doi.org/10.18632/oncotarget.4540

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Abstract

Qiongrong Chen1,3, Shumei Song1, Shaozhong Wei3, Bin Liu4, Soichiro Honjo1, Ailing Scott1, Jiankang Jin1, Lang Ma1, Haitao Zhu1, Heath D. Skinner2, Randy L. Johnson2, Jaffer A. Ajani1

1Departments of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

2Departments of Biochemistry & Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

3Hubei Cancer Hospital, Wuhan 430079, China

4Departments of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence to:

Shumei Song, e-mail: [email protected]

Jaffer A. Ajani, e-mail: [email protected]

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.


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