title: The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells.
abstract: Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor‑negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug-induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple‑negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB‑231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for patients with TNBC. However, extended preclinical trials are required to further determine the positive effects of the inhibition of autophagy on the efficacy of gemcitabine.
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Mengye
authors.initials: M
authors.lastname: He
authors.affiliation: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Yinjing
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Luoquan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Wan
authors.affiliation: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D002738:Chloroquine; D003841:Deoxycytidine; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D000093542:Gemcitabine; C546842:MTOR protein, human; C508053:ERBB2 protein, human