PMID- 32705154 OWN - NLM STAT- MEDLINE DCOM- 20210526 LR - 20211204 IS - 1791-2423 (Electronic) IS - 1019-6439 (Linking) VI - 57 IP - 3 DP - 2020 Sep TI - Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells. PG - 835-844 LID - 10.3892/ijo.2020.5089 [doi] AB - Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer and, although it is highly treatable, resistance to therapy, toxicity and side effects remain challenging. The synthetic glucocorticoid (GC) dexamethasone (Dex) is commonly used to treat ALL, the main drawback of which is the development of resistance to this treatment. The aim of the present study was to investigate potential molecular circuits mediating resistance and sensitivity to GC‑induced apoptosis in ALL. The leukaemia cell lines CEM‑C7‑14, CEM‑C1‑15 and MOLT4 treated with chloroquine (CLQ), thapsigargin (TG) and rotenone (ROT) were used to explore the roles of autophagy, endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and reactive oxygen species (ROS) generation in the response to GC treatment. ROS levels were associated with increased cell death and mitochondrial membrane potential in rotenone‑treated CEM cells. Autophagy inhibition by CLQ exhibited the strongest cytotoxic effect in GC‑resistant leukaemia. Autophagy may act as a pro‑survival mechanism in GC‑resistant leukaemia since increasing trends in beclin‑1 and microtubule‑associated protein 1 light chain 3alpha levels were detected in CEM‑C1‑15 and MOLT4 cells treated with Dex, whereas decreasing trends in these autophagy markers were observed in CEM‑C7‑14 cells. The intracellular protein levels of the ER stress markers glucose‑regulated protein (GRP)78 and GRP94 were stimulated by Dex only in the GC‑sensitive cells, suggesting a role of these chaperones in the GC‑mediated ALL cell death. Increased cell surface levels of GRP94 were recorded in CEM‑C7‑14 cells treated with combination of Dex with TG compared with those in cells treated with TG alone, whereas decreasing trends were observed in CEM‑C1‑15 cells under these conditions. Taken together, the results of the present study demonstrated that autophagy may be a pro‑survival mechanism in GC‑resistant leukaemia, and by modulating intracellular and surface GRP94 protein levels, Dex is involved in the regulation of ER stress/UPR‑dependent cell death and immune surveillance. These observations may be of clinical importance if confirmed in patients. FAU - Sudsaward, Sangkab AU - Sudsaward S AD - School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK. FAU - Khunchai, Sasiprapa AU - Khunchai S AD - Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand. FAU - Thepmalee, Chutamas AU - Thepmalee C AD - Division of Biochemistry, School of Medical Science, University of Phayao, Phayao, 56000, Thailand. FAU - Othman, Aisha AU - Othman A AD - School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK. FAU - Limjindaporn, Thawornchai AU - Limjindaporn T AD - Division of Molecular Medicine, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. FAU - Yenchitsomanus, Pa-Thai AU - Yenchitsomanus PT AD - Division of Molecular Medicine, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. FAU - Mutti, Luciano AU - Mutti L AD - Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA. FAU - Krstic-Demonacos, Marija AU - Krstic-Demonacos M AD - School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK. FAU - Demonacos, Constantinos AU - Demonacos C AD - Faculty of Biology Medicine and Health, School of Health Science, Division of Pharmacy and Optometry, University of Manchester, Manchester, M13 9PT, UK. LA - eng PT - Journal Article DEP - 20200626 PL - Greece TA - Int J Oncol JT - International journal of oncology JID - 9306042 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Heat-Shock Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (endoplasmin) RN - 03L9OT429T (Rotenone) RN - 67526-95-8 (Thapsigargin) RN - 7S5I7G3JQL (Dexamethasone) RN - 886U3H6UFF (Chloroquine) SB - IM MH - Antineoplastic Agents, Hormonal/*pharmacology/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use MH - Autophagy/drug effects/immunology MH - Cell Line, Tumor MH - Cell Survival/drug effects/immunology MH - Chloroquine/pharmacology MH - Dexamethasone/*pharmacology/therapeutic use MH - Drug Resistance, Neoplasm/drug effects/*immunology MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/drug effects/immunology MH - Heat-Shock Proteins/metabolism MH - Humans MH - Immunologic Surveillance/drug effects MH - Membrane Glycoproteins/metabolism MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/immunology/pathology MH - Rotenone/pharmacology MH - Thapsigargin/pharmacology MH - Unfolded Protein Response/drug effects/immunology OTO - NOTNLM OT - acute lymphoblastic leukaemia OT - autophagy OT - endoplasmic reticulum stress OT - glucocorticoids OT - unfolded protein response EDAT- 2020/07/25 06:00 MHDA- 2021/05/27 06:00 CRDT- 2020/07/25 06:00 PHST- 2020/01/13 00:00 [received] PHST- 2020/06/01 00:00 [accepted] PHST- 2020/07/25 06:00 [entrez] PHST- 2020/07/25 06:00 [pubmed] PHST- 2021/05/27 06:00 [medline] AID - 10.3892/ijo.2020.5089 [doi] PST - ppublish SO - Int J Oncol. 2020 Sep;57(3):835-844. doi: 10.3892/ijo.2020.5089. Epub 2020 Jun 26.