title: Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy.
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.
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.|Department of Breast Surgery, Guangxi Medical University Tumor Hospital, Nanning, China.
authors.forename: Qixing
authors.initials: Q
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Hongli
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.|Department of New Drug Screening Center, China Pharmaceutical University, Nanjing, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.|Department of New Drug Screening Center, China Pharmaceutical University, Nanjing, China.
authors.lastname: Aodengqimuge
authors.affiliation: Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University, Kaifeng, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Breast Surgery, Guangxi Medical University Tumor Hospital, Nanning, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004317:Doxorubicin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019061:src-Family Kinases
keywords: Autophagy; STAT3; Src; chemoresistance; heme oxygenase‐1