Src/STAT3‐dependent heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy

Cancer Science

Qixing Tan¹  Hongli Wang¹  Yongliang Hu¹  Meiru Hu¹  Xiaoguang Li¹  Aodengqimuge  ¹  Yuanfang Ma²  Changyuan Wei³ 

[1] Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China;Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University, Kaifeng, China;Department of Breast Surgery, Guangxi Medical University Tumor Hospital, Nanning, China

关键词: Autophagy;    chemoresistance;    heme oxygenase‐1;    Src;    STAT3;   

DOI  :  10.1111/cas.12712

来源: Wiley

【 摘 要 】

Abstract

Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of HO-1 expression in doxorubicin (DOX)-treated MDA-MB-231 human breast adenocarcinoma cells, which showed insensitivity to DOX treatment. Knockdown HO-1 expression dramatically upregulated the incidence of MDA-MB-231 cell death under DOX treatment, indicating that HO-1 functions as a critical contributor to drug resistance in MDA-MB-231 cells. We further observed that DOX exposure induced a cytoprotective autophagic flux in MDA-MB-231 cells, which was dependent on HO-1 induction. Moreover, upregulation of HO-1 expression required the activation of both signal transducer and activator of transcription (STAT)3 and its upstream regulator, protein kinase Src. Abrogating Src/STAT3 pathway activation attenuated HO-1 and autophagy induction, thus increasing the chemosensitivity of MDA-MB-231 cells. Therefore, we conclude that Src/STAT3-dependent HO-1 induction protects MDA-MB-231 breast cancer cells from DOX-induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src/STAT3/HO-1/autophagy pathway activation to DOX resistance in another breast cancer cell line, MDA-MB-468, which bears a similar phenotype to MDA-MB-231 cells. Therefore, activation of Src/STAT3/HO-1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from DOX-induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming DOX resistance in breast cancer therapeutics.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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