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

• Published in: Cancer science Vol. 106; no. 8; pp. 1023 - 1032
• Main Authors: Tan, Qixing, Wang, Hongli, Hu, Yongliang, Hu, Meiru, Li, Xiaoguang, , Aodengqimuge, Ma, Yuanfang, Wei, Changyuan, Song, Lun
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.08.2015
• Subjects: Antineoplastic Agents - pharmacology; Autophagy; Autophagy - physiology; Blotting, Western; Breast Neoplasms - metabolism; Cell Line, Tumor; chemoresistance; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - physiology; Female; Heme Oxygenase-1 - metabolism; heme oxygenase‐1; Humans; Original; Signal Transduction - physiology; Src; src-Family Kinases - metabolism; STAT3; STAT3 Transcription Factor - metabolism; Transfection; chemoresistance; heme oxygenase‐1; Src; Autophagy; STAT3
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12712

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. HO‐1‐dependent autophagy is able to attenuate DOX toxicity in the breast cancer cells, which is largely mediated by Src and STAT3 activation. Therefore Src/STAT3/HO‐1/autophagy pathway is critical for mediating chemoresistance in breast cancer cells and therapeutic strategies aimed at reducing this pathway activation may provide a potential approach to overcome DOX resistance, leading to improved clinical use of DOX in breast cancer cells.