Autophagy flux inhibition mediated by celastrol sensitized lung cancer cells to TRAIL‑induced apoptosis via regulation of mitochondrial transmembrane potential and reactive oxygen species

Nazim,Uddin Md; Yin,Honghua; Park,Sang‑Youel

doi:10.3892/mmr.2018.9757

Autophagy flux inhibition mediated by celastrol sensitized lung cancer cells to TRAIL‑induced apoptosis via regulation of mitochondrial transmembrane potential and reactive oxygen species

Authors:
- Uddin Md Nazim
- Honghua Yin
- Sang‑Youel Park
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Affiliations: Department of Biochemistry, Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea
Published online on: December 12, 2018 https://doi.org/10.3892/mmr.2018.9757
Pages: 984-993
Copyright: © Nazim 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 well known as a transmembrane cytokine and has been proposed as one of the most effective anti‑cancer therapeutic agents, owing to its efficiency to selectively induce cell death in a variety of tumor cells. Suppression of autophagy flux has been increasingly acknowledged as an effective and novel therapeutic intervention for cancer. The present study demonstrated that the anti‑cancer and anti‑inflammatory drug celastrol, through its anti‑metastatic properties, may initiate TRAIL‑mediated apoptotic cell death in lung cancer cells. This sensitization was negatively affected by N‑acetyl‑l‑cysteine, which restored the mitochondrial membrane potential (ΔΨm) and inhibited reactive oxygen species (ROS) generation. Notably, treatment with celastrol caused an increase in microtubule‑associated proteins 1A/1B light chain 3B‑II and p62 levels, whereas co‑treatment of celastrol and TRAIL increased active caspase 3 and 8 levels compared with the control, confirming inhibited autophagy flux. The combined use of TRAIL with celastrol may serve as a safe and adequate therapeutic technique for the treatment of TRAIL‑resistant lung cancer, suggesting that celastrol‑mediated autophagy flux inhibition sensitized TRAIL‑initiated apoptosis via regulation of ROS and ΔΨm.

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