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Article

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

  • Authors:
    • Sangkab Sudsaward
    • Sasiprapa Khunchai
    • Chutamas Thepmalee
    • Aisha Othman
    • Thawornchai Limjindaporn
    • Pa‑Thai Yenchitsomanus
    • Luciano Mutti
    • Marija Krstic‑Demonacos
    • Constantinos Demonacos
  • View Affiliations / Copyright

    Affiliations: School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK, Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand, Division of Biochemistry, School of Medical Science, University of Phayao, Phayao, 56000, Thailand, Division of Molecular Medicine, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA, Faculty of Biology Medicine and Health, School of Health Science, Division of Pharmacy and Optometry, University of Manchester, Manchester, M13 9PT, UK
  • Pages: 835-844
    |
    Published online on: June 26, 2020
       https://doi.org/10.3892/ijo.2020.5089
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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.
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Copy and paste a formatted citation
Spandidos Publications style
Sudsaward S, Khunchai S, Thepmalee C, Othman A, Limjindaporn T, Yenchitsomanus PT, Mutti L, Krstic‑Demonacos M and Demonacos C: Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells. Int J Oncol 57: 835-844, 2020.
APA
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, 835-844. https://doi.org/10.3892/ijo.2020.5089
MLA
Sudsaward, S., Khunchai, S., Thepmalee, C., Othman, A., Limjindaporn, T., Yenchitsomanus, P., 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". International Journal of Oncology 57.3 (2020): 835-844.
Chicago
Sudsaward, S., Khunchai, S., Thepmalee, C., Othman, A., Limjindaporn, T., Yenchitsomanus, P., 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". International Journal of Oncology 57, no. 3 (2020): 835-844. https://doi.org/10.3892/ijo.2020.5089
Copy and paste a formatted citation
x
Spandidos Publications style
Sudsaward S, Khunchai S, Thepmalee C, Othman A, Limjindaporn T, Yenchitsomanus PT, Mutti L, Krstic‑Demonacos M and Demonacos C: Endoplasmic reticulum stress, unfolded protein response and autophagy contribute to resistance to glucocorticoid treatment in human acute lymphoblastic leukaemia cells. Int J Oncol 57: 835-844, 2020.
APA
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, 835-844. https://doi.org/10.3892/ijo.2020.5089
MLA
Sudsaward, S., Khunchai, S., Thepmalee, C., Othman, A., Limjindaporn, T., Yenchitsomanus, P., 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". International Journal of Oncology 57.3 (2020): 835-844.
Chicago
Sudsaward, S., Khunchai, S., Thepmalee, C., Othman, A., Limjindaporn, T., Yenchitsomanus, P., 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". International Journal of Oncology 57, no. 3 (2020): 835-844. https://doi.org/10.3892/ijo.2020.5089
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