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极光激酶A/信号转导分子5致癌轴的分子靶向作用可恢复人乳腺癌细胞的化学敏感性。

Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells.

作者信息

Opyrchal Mateusz, Gil Malgorzata, Salisbury Jeffrey L, Goetz Mathew P, Suman Vera, Degnim Amy, McCubrey James, Haddad Tufia, Iankov Ianko, Kurokawa Chenye B, Shumacher Nicole, Ingle James N, Galanis Evanthia, D'Assoro Antonino B

机构信息

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Department of Biochemistry and Molecular Biology, Mayo Clinic College Of Medicine, Rochester, MN, USA.

出版信息

Oncotarget. 2017 Sep 1;8(53):91803-91816. doi: 10.18632/oncotarget.20610. eCollection 2017 Oct 31.

DOI:10.18632/oncotarget.20610
PMID:29207686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5710966/
Abstract

Although the majority of breast cancers initially respond to the cytotoxic effects of chemotherapeutic agents, most breast cancer patients experience tumor relapse and ultimately die because of drug resistance. Breast cancer cells undergoing epithelial to mesenchymal transition (EMT) acquire a CD44/CD24/ALDH1 cancer stem cell-like phenotype characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance and high proclivity to develop distant metastases. We uncovered in human breast tumor xenografts a novel non-mitotic role of Aurora-A kinase in promoting breast cancer metastases through activation of EMT and expansion of breast tumor initiating cells (BTICs). In this study we characterized the role of the Aurora-A/SMAD5 oncogenic axis in the induction of chemoresistance. Breast cancer cells overexpressing Aurora-A showed resistance to conventional chemotherapeutic agents, while treatment with alisertib, a selective Aurora-A kinase inhibitor, restored chemosensitivity. Significantly, SMAD5 expression was required to induce chemoresistance and maintain a breast cancer stem cell-like phenotype, indicating that the Aurora-A/SMAD5 oncogenic axis promotes chemoresistance through activation of stemness signaling. Taken together, these findings identified a novel mechanism of drug resistance through aberrant activation of the non-canonical Aurora-A/SMAD5 oncogenic axis in breast cancer.

摘要

尽管大多数乳腺癌最初对化疗药物的细胞毒性作用有反应，但大多数乳腺癌患者会经历肿瘤复发，最终因耐药性而死亡。经历上皮-间质转化（EMT）的乳腺癌细胞获得了一种CD44/CD24/ALDH1癌干细胞样表型，其特征是肿瘤自我更新能力增强、内在耐药性以及远处转移的高倾向性。我们在人乳腺肿瘤异种移植模型中发现，Aurora-A激酶在通过激活EMT和扩增乳腺肿瘤起始细胞（BTIC）促进乳腺癌转移方面具有一种新的非有丝分裂作用。在本研究中，我们阐述了Aurora-A/SMAD5致癌轴在诱导化疗耐药中的作用。过表达Aurora-A的乳腺癌细胞对传统化疗药物具有抗性，而用选择性Aurora-A激酶抑制剂alisertib治疗可恢复化疗敏感性。重要的是，诱导化疗耐药性并维持乳腺癌干细胞样表型需要SMAD5表达，这表明Aurora-A/SMAD5致癌轴通过激活干性信号传导促进化疗耐药。综上所述，这些发现确定了一种通过乳腺癌中非经典Aurora-A/SMAD5致癌轴异常激活导致耐药的新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/0bf3a1153097/oncotarget-08-91803-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/8d2c31f7219f/oncotarget-08-91803-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/678b03ab5c52/oncotarget-08-91803-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/d43291de842b/oncotarget-08-91803-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/1476941223b3/oncotarget-08-91803-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/5b8b906a0ecf/oncotarget-08-91803-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/0bf3a1153097/oncotarget-08-91803-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/8d2c31f7219f/oncotarget-08-91803-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/678b03ab5c52/oncotarget-08-91803-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/d43291de842b/oncotarget-08-91803-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/c7b3db989311/oncotarget-08-91803-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/1476941223b3/oncotarget-08-91803-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/5b8b906a0ecf/oncotarget-08-91803-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/904f/5710966/0bf3a1153097/oncotarget-08-91803-g007.jpg

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