1. Src Inhibition Can Synergize with Gemcitabine and Reverse Resistance in Triple Negative Breast Cancer Cells via the AKT/c-Jun Pathway
- Author
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Zhonghua Tao, Chen Lin, Xichun Hu, Jian Zhang, Mingming Liu, and Zhenhua Wu
- Subjects
0301 basic medicine ,Oncology ,Carcinogenesis ,Survivin ,Cancer Treatment ,lcsh:Medicine ,Apoptosis ,Triple Negative Breast Neoplasms ,Deoxycytidine ,Biochemistry ,Inhibitor of Apoptosis Proteins ,0302 clinical medicine ,Spectrum Analysis Techniques ,Cell Movement ,Animal Cells ,Cancer Stem Cells ,Antineoplastic Combined Chemotherapy Protocols ,Breast Tumors ,Tumor Cells, Cultured ,Medicine and Health Sciences ,Small interfering RNAs ,Enzyme Inhibitors ,RNA, Small Interfering ,lcsh:Science ,bcl-2-Associated X Protein ,Multidisciplinary ,biology ,Cell Death ,Chemistry ,Stem Cells ,Drug Synergism ,Flow Cytometry ,Cancer Cell Migration ,Gene Expression Regulation, Neoplastic ,Nucleic acids ,Cell Motility ,Hyaluronan Receptors ,src-Family Kinases ,Cell Processes ,Spectrophotometry ,030220 oncology & carcinogenesis ,Female ,Matrix Metalloproteinase 3 ,RNA Interference ,Cytophotometry ,Stem cell ,Cellular Types ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src ,Research Article ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,bcl-X Protein ,Cell Migration ,Transfection ,Research and Analysis Methods ,03 medical and health sciences ,Cancer stem cell ,Internal medicine ,Breast Cancer ,medicine ,Genetics ,Humans ,Benzodioxoles ,Non-coding RNA ,Molecular Biology Techniques ,Protein kinase B ,Molecular Biology ,Cell Proliferation ,Biology and life sciences ,Cell growth ,CD44 ,lcsh:R ,JNK Mitogen-Activated Protein Kinases ,Cancers and Neoplasms ,Cell Biology ,Gemcitabine ,Gene regulation ,030104 developmental biology ,Drug Resistance, Neoplasm ,Focal Adhesion Kinase 1 ,biology.protein ,Cancer research ,Quinazolines ,RNA ,lcsh:Q ,Gene expression ,Octamer Transcription Factor-3 ,Proto-Oncogene Proteins c-akt ,Developmental Biology - Abstract
Purpose Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells. Methods and Results By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway. Conclusion In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway.
- Published
- 2016