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Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells

Sudsaward, S; Khunchai, S; Thepmalee, C; Othman, A; Limjindaporn, T; Yenchitsomanus, P‑T; Mutti, L; Krstic‑Demonacos, M; Demonacos, C

Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells Thumbnail


Authors

S Sudsaward

S Khunchai

C Thepmalee

A Othman

T Limjindaporn

P‑T Yenchitsomanus

L Mutti

C Demonacos



Abstract

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 3α 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.

Citation

Sudsaward, S., Khunchai, S., Thepmalee, C., Othman, A., Limjindaporn, T., Yenchitsomanus, P., …Demonacos, C. (2020). Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells. International Journal of Oncology, 57(3), 835-844. https://doi.org/10.3892/ijo.2020.5089

Journal Article Type Article
Acceptance Date May 29, 2020
Online Publication Date Jun 26, 2020
Publication Date Jun 26, 2020
Deposit Date Jul 10, 2020
Publicly Available Date Dec 26, 2020
Journal International Journal of Oncology
Print ISSN 1019-6439
Electronic ISSN 1791-2423
Publisher Spandidos Publications
Volume 57
Issue 3
Pages 835-844
DOI https://doi.org/10.3892/ijo.2020.5089
Keywords Cancer Research, Oncology
Publisher URL https://doi.org/10.3892/ijo.2020.5089
Related Public URLs http://www.spandidos-publications.com/ijo/
Additional Information Additional Information : ** From Crossref via Jisc Publications Router **Journal IDs: pissn 1019-6439; eissn 1791-2423 **History: issued 26-06-2020; published_online 26-06-2020
Funders : Royal Thai Government Scholarships, Ministry of Science and Technology, Thailand;Staff Development Fund, Naresuan University;Thailand Research Fund (TRF);Thailand Research Fund -International Research Network;Siriraj Research Fund;Siriraj Chalermprakiat Grant;Thailand Research Fund -Royal Golden Jubilee Ph.D. Scholarship
Grant Number: IRG5980006
Grant Number: IRN58W001
Grant Number: R016034008
Grant Number: PHD/0044/2556

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