title: Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells.
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.
authors.affiliation: a 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Xu
authors.forename: Jiajun
authors.initials: J
authors.lastname: Xie
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Guan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Hou
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Xin
authors.initials: X
authors.lastname: Shu
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Si
authors.forename: Ya
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Kang
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fang
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 3-MA, 3-methyladenine; CQ, chloroquine; Dex, dexamethasone; Dox, doxorubicin; LC3, microtubule-associated protein 1 light chain 3; MDC, monodansylcadaverine; OCT, optimum cutting temperature; Rapa, rapamycin; WST-8, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H- tetrazolium, monosodium salt; apoptosis; autophagy; dexamethasone; glucocorticoid resistance; lymphoid malignancy; mTOR, mammalian target of rapamycin