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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/?-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.

SUBMITTER: Chen Q

PROVIDER: S-EPMC4694873 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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

Chen Qiongrong Q Song Shumei S Wei Shaozhong S Liu Bin B Honjo Soichiro S Scott Ailing A Jin Jiankang J Ma Lang L Zhu Haitao H Skinner Heath D HD Johnson Randy L RL Ajani Jaffer A JA

Oncotarget 20150901 28

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 apopt ...[more]

PMID: 26317542

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

Publications

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

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