Version 1
: Received: 14 December 2020 / Approved: 15 December 2020 / Online: 15 December 2020 (12:09:09 CET)
How to cite:
Zinnah, K.; Seol, J.; Park, S. Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux. Preprints2020, 2020120376. https://doi.org/10.20944/preprints202012.0376.v1
Zinnah, K.; Seol, J.; Park, S. Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux. Preprints 2020, 2020120376. https://doi.org/10.20944/preprints202012.0376.v1
Zinnah, K.; Seol, J.; Park, S. Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux. Preprints2020, 2020120376. https://doi.org/10.20944/preprints202012.0376.v1
APA Style
Zinnah, K., Seol, J., & Park, S. (2020). Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux. Preprints. https://doi.org/10.20944/preprints202012.0376.v1
Chicago/Turabian Style
Zinnah, K., Jae-Won Seol and Sang-Youel Park. 2020 "Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux" Preprints. https://doi.org/10.20944/preprints202012.0376.v1
Abstract
Autophagy, an alternative cell death mechanism, is also termed programmed cell death type II. Autophagy in cancer treatment needs to be regulated. In our study, autophagy inhibition by desipramine or the autophagy inhibitor chloroquine (CQ) enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 [death receptor (DR5)] expression and subsequently TRAIL-induced apoptosis in TRAIL-resistant A549 lung cancer cells. Genetic inhibition of DR5 substantially reduced desipramine-enhanced TRAIL-mediated apoptosis, proving that DR5 was required to increase TRAIL sensitivity in TRAIL-resistant cancer cells. Desipramine treatment upregulated p62 expression and promoted conversion of light chain 3 (LC3)-I to its lipid-conjugated form, LC3-II, indicating that autophagy inhibition occurred at the final stages of autophagic flux. Transmission electron microscopy analysis showed the presence of condensed autophagosomes, which resulted from the late stages of autophagy inhibition by desipramine. TRAIL, in combination with desipramine or CQ, augmented the expression of apoptosis-related proteins cleaved caspase-8 and cleaved caspase-3. Our results contributed to the understanding of the mechanism underlying the synergistic anti-cancer effect of desipramine and TRAIL and presented a novel mechanism of DR5 upregulation. These findings demonstrated that autophagic flux inhibition by desipramine potentiated TRAIL-induced apoptosis, suggesting that appropriate regulation of autophagy is required for sensitizing TRAIL-resistant cancer cells to TRAIL-mediated apoptosis.
Keywords
Desipramine; Autophagy; Apoptosis; Death receptor-5; TRAIL
Subject
Medicine and Pharmacology, Immunology and Allergy
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
