Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells

  • Authors:
    • Sung-Chul Lim
    • Ho Jong Jeon
    • Keun Hong Kee
    • Mi Ja Lee
    • Ran Hong
    • Song Iy Han
  • View Affiliations

  • Published online on: September 20, 2016     https://doi.org/10.3892/ijo.2016.3699
  • Pages: 1983-1990
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Abstract

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, a number of cancer cells demonstrate TRAIL resistance. To date, various molecular targets leading to TRAIL resistance have been elucidated by many researchers, but the mechanisms involved are still not fully understood. In the present study, we obtained TRAIL-resistant cells from the human hepatocellular carcinoma cell line HepG2 by exposing cells to recombinant human TRAIL (rhTRAIL), and determined a mechanism for TRAIL resistance. The selected TRAIL-resistant cells (HepG2-TR) were insensitive to rhTRAIL and triggered autophagy in response to rhTRAIL. The inhibition of autophagy by 3-methyladenine or the knockdown of ATG5 partially restored rhTRAIL-induced apoptosis and cytotoxicity, indicating that protective autophagy occurred in the cells. Notably, rhTRAIL-induced autophagy was mediated through DR4 in HepG2-TR cells, but not in parental HepG2 cells. In addition, the c-Jun N-terminal kinase was involved in DR4-mediated autophagy in HepG2-TR cells. Our results suggest a novel mechanism of TRAIL resistance which is regulated through alterations in DR4 function, which may extend our understanding of the mechanisms of TRAIL resistance.
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November-2016
Volume 49 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Lim S, Jeon HJ, Kee KH, Lee MJ, Hong R and Han SI: Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells. Int J Oncol 49: 1983-1990, 2016.
APA
Lim, S., Jeon, H.J., Kee, K.H., Lee, M.J., Hong, R., & Han, S.I. (2016). Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells. International Journal of Oncology, 49, 1983-1990. https://doi.org/10.3892/ijo.2016.3699
MLA
Lim, S., Jeon, H. J., Kee, K. H., Lee, M. J., Hong, R., Han, S. I."Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells". International Journal of Oncology 49.5 (2016): 1983-1990.
Chicago
Lim, S., Jeon, H. J., Kee, K. H., Lee, M. J., Hong, R., Han, S. I."Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells". International Journal of Oncology 49, no. 5 (2016): 1983-1990. https://doi.org/10.3892/ijo.2016.3699