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Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway

  • Authors:
    • Su‑Hoon Lee
    • Hyun‑Jung Moon
    • Young‑Shin Lee
    • Chi‑Dug Kang
    • Sun‑Hee Kim
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Gyeongsangnam‑do 626‑870, Republic of Korea
    Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1136-1148
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    Published online on: June 25, 2020
       https://doi.org/10.3892/or.2020.7662
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Abstract

Hepatocellular carcinoma (HCC) is the most commonly diagnosed primary liver malignancy. The limited success with relapse of the disease in HCC therapy is frequently associated with the acquired resistance to anticancer drugs. To develop a strategy and design for overcoming the resistance of HCC cells to TNF‑related apoptosis inducing ligand (TRAIL)‑induced cell death, we evaluated the efficacy of a non‑steroidal anti‑inflammatory drug (NSAID) in combination with TRAIL against TRAIL‑resistant HCC cells expressing a high level of CD44. We revealed by MTT and western blotting, respectively, that celecoxib (CCB), an NSAID, and 2,5‑dimethyl celecoxib (DMC), a non‑cyclooxygenase (COX)‑2 inhibitor analog of CCB, were able to sensitize TRAIL‑resistant HCC cells to TRAIL, implicating a COX‑independent mechanism. CCB dose‑dependently enhanced LC3‑II and reduced p62 levels through AMPK activation and inhibition of the Akt/mTOR pathway and upregulated expression of ATF4/CHOP, leading to activation of endoplasmic reticulum (ER) stress‑dependent autophagy. The TRAIL sensitization capacity of CCB in TRAIL‑resistant HCC cells was abrogated by an ER stress inhibitor. In addition, we also revealed by flow cytometry and western blotting, respectively, that accelerated downregulation of TRAIL‑mediated c‑FLIP expression, DR5 activation and CD44 degradation/downregulation by NSAID resulted in activation of caspases and poly(ADP‑ribose) polymerase (PARP), leading to the sensitization of TRAIL‑resistant HCC cells to TRAIL and thereby reversal of TRAIL resistance. From these results, we propose that NSAID in combination with TRAIL may improve the antitumor activity of TRAIL in TRAIL‑resistant HCC, and this approach may serve as a novel strategy that maximizes the therapeutic efficacy of TRAIL for clinical application.
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Copy and paste a formatted citation
Spandidos Publications style
Lee SH, Moon HJ, Lee YS, Kang CD and Kim SH: Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway. Oncol Rep 44: 1136-1148, 2020.
APA
Lee, S., Moon, H., Lee, Y., Kang, C., & Kim, S. (2020). Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway. Oncology Reports, 44, 1136-1148. https://doi.org/10.3892/or.2020.7662
MLA
Lee, S., Moon, H., Lee, Y., Kang, C., Kim, S."Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway". Oncology Reports 44.3 (2020): 1136-1148.
Chicago
Lee, S., Moon, H., Lee, Y., Kang, C., Kim, S."Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway". Oncology Reports 44, no. 3 (2020): 1136-1148. https://doi.org/10.3892/or.2020.7662
Copy and paste a formatted citation
x
Spandidos Publications style
Lee SH, Moon HJ, Lee YS, Kang CD and Kim SH: Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway. Oncol Rep 44: 1136-1148, 2020.
APA
Lee, S., Moon, H., Lee, Y., Kang, C., & Kim, S. (2020). Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway. Oncology Reports, 44, 1136-1148. https://doi.org/10.3892/or.2020.7662
MLA
Lee, S., Moon, H., Lee, Y., Kang, C., Kim, S."Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway". Oncology Reports 44.3 (2020): 1136-1148.
Chicago
Lee, S., Moon, H., Lee, Y., Kang, C., Kim, S."Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway". Oncology Reports 44, no. 3 (2020): 1136-1148. https://doi.org/10.3892/or.2020.7662
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