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Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation

  • Authors:
    • Kazi Mohammad Ali Zinnah
    • Jae‑Won Seol
    • Sang‑Youel Park
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    Affiliations: Biosafety Research Institute, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea
    Copyright: © Zinnah et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 795-805
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    Published online on: June 5, 2020
       https://doi.org/10.3892/ijmm.2020.4635
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Abstract

Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) is a potential target for cancer therapy, owing to its ability to selectively kill cancer cells without causing significant toxicity to normal cells. However, due to the lack of death receptor expression, cancer cells can become highly resistant to TRAIL. Hence, it is vital to develop agents that restore TRAIL efficacy. Sertraline is an antidepressant drug with anticancer properties. To the best of our knowledge, this is the first study to demonstrate that sertraline inhibits autophagic flux and increases the expression of death receptor 5 (DR5) on TRAIL‑resistant lung cancer cells. Inhibition of autophagy using autophagy inhibitors 3‑methyladenine and chloroquine upregulated the expression of DR5 and enhanced TRAIL‑induced apoptosis, as confirmed by the increase of pro‑apoptotic proteins caspase‑8 and caspase‑3. Silencing DR5 expression using DR5 small interfering RNA prevented sertraline‑induced TRAIL‑mediated apoptosis, indicating the role of DR5 in TRAIL‑mediated apoptosis. Overall, sertraline enhanced TRAIL‑mediated apoptosis via the downregulation of AMP‑activated protein kinase phosphorylation, resulting in the inhibition of autophagic flux, upregulation of DR5 expression, and activation of the apoptotic caspase cascade. These data suggested that sertraline could be used to sensitize human lung cancer cells to TRAIL, while also serving as a therapeutic option in cancer patients with depression.
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Copy and paste a formatted citation
Spandidos Publications style
Zinnah KM, Seol JW and Park SY: Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med 46: 795-805, 2020.
APA
Zinnah, K.M., Seol, J., & Park, S. (2020). Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. International Journal of Molecular Medicine, 46, 795-805. https://doi.org/10.3892/ijmm.2020.4635
MLA
Zinnah, K. M., Seol, J., Park, S."Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation". International Journal of Molecular Medicine 46.2 (2020): 795-805.
Chicago
Zinnah, K. M., Seol, J., Park, S."Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation". International Journal of Molecular Medicine 46, no. 2 (2020): 795-805. https://doi.org/10.3892/ijmm.2020.4635
Copy and paste a formatted citation
x
Spandidos Publications style
Zinnah KM, Seol JW and Park SY: Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med 46: 795-805, 2020.
APA
Zinnah, K.M., Seol, J., & Park, S. (2020). Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. International Journal of Molecular Medicine, 46, 795-805. https://doi.org/10.3892/ijmm.2020.4635
MLA
Zinnah, K. M., Seol, J., Park, S."Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation". International Journal of Molecular Medicine 46.2 (2020): 795-805.
Chicago
Zinnah, K. M., Seol, J., Park, S."Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation". International Journal of Molecular Medicine 46, no. 2 (2020): 795-805. https://doi.org/10.3892/ijmm.2020.4635
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