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

被引：31

作者：

Chen, Qiongrong ^{[1
,4
]}

Song, Shumei ^{[1
]}

Wei, Shaozhong ^{[4
]}

Liu, Bin ^{[5
]}

Honjo, Soichiro ^{[1
]}

Scott, Ailing ^{[1
]}

Jin, Jiankang ^{[1
]}

Ma, Lang ^{[1
]}

Zhu, Haitao ^{[1
]}

Skinner, Heath D. ^{[2
,3
]}

Johnson, Randy L. ^{[2
,3
]}

Ajani, Jaffer A. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Biochem, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Mol Biol, Houston, TX 77030 USA

[4] Hubei Canc Hosp, Wuhan 430079, Peoples R China

[5] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

来源：

ONCOTARGET | 2015年 / 6卷 / 28期

关键词：

esophageal cancer; stemness pathways; cancer stem cells; ABT-263; 5-fluorouracil; NAVITOCLAX ABT-263; TGF-BETA; RESISTANCE; BCL-2; EXPRESSION; CELLS; YAP1; ADENOCARCINOMA; RADIATION; HEDGEHOG;

D O I：

10.18632/oncotarget.4540

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 ABT263 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/beta-catenin and YAP/SOX9 axes. Furthermore, ABT-263 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.

引用

页码：25883 / 25896

页数：14

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