The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells
Triple-negative breast cancerĀ (TNBC), which is estrogen receptorĀ (ER)-negative, progesterone receptornegative 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 triplenegative 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-MB231 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.
Document Type: Research Article
Affiliations: 1: Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China 2: Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China
Publication date: 01 January 2014
- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases. - Editorial Board
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