Open Access

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
  • View Affiliations

  • Published online on: June 5, 2020     https://doi.org/10.3892/ijmm.2020.4635
  • Pages: 795-805
  • Copyright: © Zinnah et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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August-2020
Volume 46 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos
Zinnah KM, Seol J and Park S: 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