Title:An Antidepressant Drug Increased TRAIL Receptor-2 Expression and Sensitized
Lung Cancer Cells to TRAIL-induced Apoptosis
Volume: 23
Issue: 20
Author(s): Kazi Mohammad Ali Zinnah, Ali Newaz Munna, Jae-Won Seol, Byung-Yong Park and Sang-Youel Park*
Affiliation:
- Biosafety Research Institute, College of Veterinary Medicine, Jeonbuk National University, Gobong ro, Iksan, Jeonbuk, 54596, South
Korea
Keywords:
Desipramine, autophagy, apoptosis, death receptor-5, TRAIL, antidepressant drug.
Abstract:
Background: TRAIL has emerged as a promising therapeutic target due to its ability to selectively
induce apoptosis in cancer cells while sparing normal cells. Autophagy, a highly regulated cellular recycling
mechanism, is known to play a cell survival role by providing a required environment for the cell. Recent studies
suggest that autophagy plays a significant role in increasing TRAIL resistance in certain cancer cells. Thus, regulating
autophagy in TRAIL-mediated cancer therapy is crucial for its role in cancer treatment.
Objective: Our study explored whether the antidepressant drug desipramine could enhance the ability of TRAIL
to kill cancer cells by inhibiting autophagy.
Methods: The effect of desipramine on TRAIL sensitivity was examined in various lung cancer cell lines. Cell
viability was measured by morphological analysis, trypan blue exclusion, and crystal violet staining. Flow cytometry
analysis was carried out to measure apoptosis with annexin V-PI stained cells. Western blotting, rtPCR, and
immunocytochemistry were carried out to measure autophagy and death receptor expression. TEM was carried
out to detect autophagy inhibition.
Results: Desipramine treatment increased the TRAIL sensitivity in all lung cancer cell lines. Mechanistically,
desipramine treatment induced death receptor expression to increase TRAIL sensitivity. This effect was confirmed
when the genetic blockade of DR5 reduced the effect of desipramine in enhanced TRAIL-mediated cell
death. Further investigation revealed that desipramine treatment increased the LC3 and p62 levels, indicating the
inhibition of lysosomal degradation of autophagy. Notably, TRAIL, in combination with either desipramine or the
autophagy inhibitor chloroquine, exhibited enhanced cytotoxicity compared to TRAIL treatment alone.
Conclusion: Our findings revealed the potential of desipramine to induce TRAIL-mediated cell death by autophagy
impairment. This discovery suggests its therapeutic potential for inducing TRAIL-mediated cell death by
increasing the expression of death receptors, which is caused by impairing autophagy.
