Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells |
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Authors: | Lei Jiang Lingzhi Xu Jiajun Xie Sisi Li Yanchun Guan Yan Zhang Zhijie Hou Tao Guo Xin Shu Chang Wang Wenjun Fan Yang Si Ya Yang Zhijie Kang Meiyun Fang Quentin Liu |
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Affiliation: | 1.Institute of Cancer Stem Cell; Dalian Medical University; Dalian, China; State Key Laboratory of Oncology in South China; Cancer Center; Sun Yat-sen University; Guangzhou, China;2.Department of Hematology; The First Affiliated Hospital; Dalian Medical University; Dalian, China;3.Department of Hematology; The Fourth Affiliated Hospital; Anhui Medical University; Hefei, China |
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Abstract: | Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance. |
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Keywords: | autophagy apoptosis dexamethasone glucocorticoid resistance lymphoid malignancy |
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