title: Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis.
abstract: Chemotherapy is the mainstay of systemic treatment for triple negative breast cancer (TNBC); however, the development of drug resistance limits its effectiveness. Therefore, we investigated the underlying mechanism for drug resistance and potential approaches to overcome it for a more effective treatment for TNBCs. Using a pulse-stimulated selection strategy to mimic chemotherapy administration in the clinic, we developed a new paclitaxel-resistant MDA-MB-231 cell line and analyzed these cells for changes in autophagy activity, and the role and mechanisms of the increased autophagy in promoting drug resistance were determined. We found that the pulse-stimulated selection strategy with paclitaxel resulted in MDA-MB-231 variant cells with enhanced resistance to paclitaxel. These resistant cells were found to have enhanced basal autophagy activity, which confers a cytoprotective function under paclitaxel treatment stress. Inhibition of autophagy enhanced paclitaxel-induced cell death in these paclitaxel-resistant cells. We further revealed that up-regulated autophagy in resistant cells enhanced the clearance of damaged mitochondria. Last, we showed that the paclitaxel-resistant cancer cells acquired cross resistance to epirubicin and cisplatin. Together, these results suggest that combining autophagy inhibition with chemotherapy may be an effective strategy to improve treatment outcome in paclitaxel-resistant TNBC patients.
authors: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
authors: Jian
authors: J
authors: Wen
authors: Syn
authors: S
authors: Yeo
authors: Chenran
authors: C
authors: Wang
authors: Song
authors: S
authors: Chen
authors: Shaogang
authors: S
authors: Sun
authors: Michael A
authors: MA
authors: Haas
authors: Wei
authors: W
authors: Tu
authors: Feng
authors: F
authors: Jin
authors: Jun-Lin
authors: JL
authors: Guan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D017239:Paclitaxel; D002945:Cisplatin
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