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The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells.
Int J Mol Med. 2014 Jul; 34(1):276-82.IJ

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+Show Affiliations

Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.Institute of Immunology, Zhejiang University, Hangzhou 310003, P.R. China.Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24804820

Citation

Chen, Ming, et al. "The Cytoprotective Role of Gemcitabine-induced Autophagy Associated With Apoptosis Inhibition in Triple-negative MDA-MB-231 Breast Cancer Cells." International Journal of Molecular Medicine, vol. 34, no. 1, 2014, pp. 276-82.
Chen M, He M, Song Y, et al. The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells. Int J Mol Med. 2014;34(1):276-82.
Chen, M., He, M., Song, Y., Chen, L., Xiao, P., Wan, X., Dai, F., & Shen, P. (2014). The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells. International Journal of Molecular Medicine, 34(1), 276-82. https://doi.org/10.3892/ijmm.2014.1772
Chen M, et al. The Cytoprotective Role of Gemcitabine-induced Autophagy Associated With Apoptosis Inhibition in Triple-negative MDA-MB-231 Breast Cancer Cells. Int J Mol Med. 2014;34(1):276-82. PubMed PMID: 24804820.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells. AU - Chen,Ming, AU - He,Mengye, AU - Song,Yinjing, AU - Chen,Luoquan, AU - Xiao,Peng, AU - Wan,Xiaopeng, AU - Dai,Feng, AU - Shen,Peng, Y1 - 2014/05/06/ PY - 2013/09/12/received PY - 2014/04/28/accepted PY - 2014/5/9/entrez PY - 2014/5/9/pubmed PY - 2014/12/31/medline SP - 276 EP - 82 JF - International journal of molecular medicine JO - Int J Mol Med VL - 34 IS - 1 N2 - 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. SN - 1791-244X UR - https://www.unboundmedicine.com/medline/citation/24804820/The_cytoprotective_role_of_gemcitabine_induced_autophagy_associated_with_apoptosis_inhibition_in_triple_negative_MDA_MB_231_breast_cancer_cells_ L2 - http://www.spandidos-publications.com/ijmm/34/1/276 DB - PRIME DP - Unbound Medicine ER -