Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines

  • Authors:
    • Junji Kouhara
    • Tatsushi Yoshida
    • Susumu Nakata
    • Mano Horinaka
    • Miki Wakada
    • Yuji Ueda
    • Hisakazu Yamagishi
    • Toshiyuki Sakai
  • View Affiliations

  • Published online on: March 1, 2007     https://doi.org/10.3892/ijo.30.3.679
  • Pages: 679-687
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Abstract

Fenretinide (N-[4-Hydroxyphenyl]retinamide; 4HPR) is a semisynthetic retinoid that induces apoptosis in a variety of malignancies. Fenretinide has been examined in clinical trials as a cancer chemopreventive and chemotherapeutic agent. Oxidative stress induced by fenretinide has been shown to mediate apoptosis through a mitochondrial pathway by the induction of a transcription factor CCAAT/enhancer binding protein homologous protein (CHOP) and Bak. In this study, we report that fenretinide induces death receptor 5 (DR5)/TRAIL-R2 up-regulation via the induction of the transcription factor CHOP in colon cancer cell lines. Fenretinide induced DR5 expression at protein and mRNA levels. Furthermore, fenretinide increased DR5 promoter activity and the enhanced activity decreased by mutation of the CHOP binding site. CHOP was also up-regulated by fenretinide at the promoter level. We also showed that combined treatment with fenretinide and TRAIL induced synergistic apoptosis in colon cancer cell lines. The synergistic apoptosis was markedly blocked by DR5/Fc chimeric protein. Fenretinide and TRAIL cooperatively activated caspase-3, -8, -10 and -9 and cleavage of Bid and PARP, and this activation was also blocked in the presence of DR5/Fc chimeric protein. These results indicate that fenretinide-induced apoptosis is sensitized by TRAIL. Therefore, combined treatment with fenretinide and TRAIL might be a promising model for the treatment of colorectal cancer.

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March 2007
Volume 30 Issue 3

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

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Spandidos Publications style
Kouhara J, Yoshida T, Nakata S, Horinaka M, Wakada M, Ueda Y, Yamagishi H and Sakai T: Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines. Int J Oncol 30: 679-687, 2007
APA
Kouhara, J., Yoshida, T., Nakata, S., Horinaka, M., Wakada, M., Ueda, Y. ... Sakai, T. (2007). Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines. International Journal of Oncology, 30, 679-687. https://doi.org/10.3892/ijo.30.3.679
MLA
Kouhara, J., Yoshida, T., Nakata, S., Horinaka, M., Wakada, M., Ueda, Y., Yamagishi, H., Sakai, T."Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines". International Journal of Oncology 30.3 (2007): 679-687.
Chicago
Kouhara, J., Yoshida, T., Nakata, S., Horinaka, M., Wakada, M., Ueda, Y., Yamagishi, H., Sakai, T."Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines". International Journal of Oncology 30, no. 3 (2007): 679-687. https://doi.org/10.3892/ijo.30.3.679