COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis

  • Authors:
    • Yutaka Yamanaka
    • Katsuya Shiraki
    • Tomoko Inoue
    • Kazumi Miyashita
    • Hiroyuki Fuke
    • Yumi Yamaguchi
    • Norihiko Yamamoto
    • Keiichi Ito
    • Kazushi Sugimoto
    • Takeshi Nakano
  • View Affiliations

  • Published online on: July 1, 2006     https://doi.org/10.3892/ijmm.18.1.41
  • Pages: 41-47
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Abstract

Cyclooxygenase (COX)-2 is upregulated in a variety of human cancers, including in hepatocellular carcinoma (HCC), whereas it is undetectable in most normal tissue. Evidence suggests that COX-2 is likely to be involved in hepatocarcinogenesis and, thus, COX-2 may be involved in an early process in carcinogenesis, dedifferentiation. To address this possibility, we investigated the effect of COX-2 inhibitors on TNF-related apoptosis, inducing ligand (TRAIL) sensitivity and its molecular mechanisms, with special attention to anti-apoptotic proteins. We used the highly selective COX-2 inhibitors, NS398 and CAY10404. We also used the MTT assay and cytological analysis of DAPI-stained DNA to assess viability and apoptosis in two HCC cells (SK-Hep1 and HLE). In order to ask what led to increased sensitivity to TRAIL in HCC cells, cell surface expression of TRAIL and TRAIL-receptors was investigated using flow cytometry analysis. Expression of survivin, X-chromosome-linked IAP (XIAP), Bcl-xL, AKT and phospho-AKT was also investigated using immunoblotting. COX-2 inhibitors resulted in a concentration-dependent decrease in cell viability in the two HCC cell lines tested. Subtoxic levels of COX-2 inhibitors did not significantly augment TNFα-induced apoptosis but did dramatically enhance TRAIL-induced apoptosis in both cell lines. TRAIL receptor 2/death receptor 5 (TRAIL-R2/DR5) expression was significantly up-regulated in SH-Hep1 and HLE cells. TRAIL receptor 1/death receptor 4 (TRAIL-R1/DR4) expression was up-regulated only in SK-Hep1. Expression of survivin and Bcl-xL was down-regulated in SK-Hep1 and HLE cells in the presence of CAY10404 but XIAP was not affected. Expression of survivin, Bcl-xL and XIAP was down-regulated in SK-Hep1 cells in the presence of NS398. Survivin expression was also down-regulated in the presence of NS398 in HLE cells. Finally, NS398 also decreased phospho-AKT in SK-Hep1 cells. These results demonstrate that COX-2 inhibitors can induce apoptosis and augment TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of both survivin and AKT signaling.

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July 2006
Volume 18 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Yamanaka Y, Shiraki K, Inoue T, Miyashita K, Fuke H, Yamaguchi Y, Yamamoto N, Ito K, Sugimoto K, Nakano T, Nakano T, et al: COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis. Int J Mol Med 18: 41-47, 2006
APA
Yamanaka, Y., Shiraki, K., Inoue, T., Miyashita, K., Fuke, H., Yamaguchi, Y. ... Nakano, T. (2006). COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis. International Journal of Molecular Medicine, 18, 41-47. https://doi.org/10.3892/ijmm.18.1.41
MLA
Yamanaka, Y., Shiraki, K., Inoue, T., Miyashita, K., Fuke, H., Yamaguchi, Y., Yamamoto, N., Ito, K., Sugimoto, K., Nakano, T."COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis". International Journal of Molecular Medicine 18.1 (2006): 41-47.
Chicago
Yamanaka, Y., Shiraki, K., Inoue, T., Miyashita, K., Fuke, H., Yamaguchi, Y., Yamamoto, N., Ito, K., Sugimoto, K., Nakano, T."COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis". International Journal of Molecular Medicine 18, no. 1 (2006): 41-47. https://doi.org/10.3892/ijmm.18.1.41