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Death Receptors in Cancer Therapy pp 175–187Cite as

Regulation of Trail Receptor Expression in Human Melanoma

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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

In previous studies we have shown that the level of expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor R2 was a major determinant of the sensitivity of melanoma cell lines to TRAIL-induced apoptosis. Transcriptional events regulating TRAIL death receptor expression have been the focus of much study, but our investigations point to a more important role for posttranscriptional events in regulation of TRAIL death receptors. First, although there was a wide variation in TRAIL-R2 expression between melanoma cell lines, this did not correlate with mRNA expression assessed by real-time PCR. Similarly, early passage primary cultures from patients tended to have low TRAIL-R2 protein expression compared to cells in later passage cultures, even though TRAIL-R2 mRNA expression was similar in early and late passages. Second, generation of TRAIL-resistant melanoma lines by culture in TRAIL was also associated with decreased expression of TRAIL-R2 protein, but TRAIL-R2 mRNA levels were similar to those in parental high-TRAIL-R2 expressing cells. The latter model was used to explore post-transcriptional regulation of TRAIL-R2. Expression from a luciferase reporter gene construct with the 3′ untranslated region (UTR) (but not the 5′ UTR) of TRAIL-R2 was suppressed when transfected into the TRAIL-selected (resistant) melanoma lines and in early passage (resistant) primary melanoma cultures. RNA gel shift assays demonstrated protein(s) binding to the 3′UTR but not the 5′UTR of TRAIL-R2 mRNA. These results suggest that TRAIL-R2 expression in melanoma cell lines is determined in large part by posttranscriptional events and that protein(s) binding to the 3′UTR region of TRAIL-R2 mRNA may play a key role in this regulation. Decoy receptors appeared to play little or no role in regulation of TRAIL-mediated apoptosis of melanoma.

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Authors and Affiliations

  1. Immunology and Oncology Unit, David Maddison Building, University of Newcastle, Newcastle, New South Wales, Australia

    Peter Hersey FRACP, DPhil

  2. David Maddison Building, University of Newcastle, Newcastle, New South Wales, Australia

    Si Yi Zhang PhD & Xu Dong Zhang MD, PhD

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  1. Peter Hersey FRACP, DPhil
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  2. Si Yi Zhang PhD
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  3. Xu Dong Zhang MD, PhD
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Editors and Affiliations

  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  3. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

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© 2005 Humana Press Inc., Totowa, NJ

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Hersey, P., Zhang, S.Y., Zhang, X.D. (2005). Regulation of Trail Receptor Expression in Human Melanoma. In: El-Deiry, W.S. (eds) Death Receptors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-851-X:175

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  • DOI: https://doi.org/10.1385/1-59259-851-X:175

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-172-1

  • Online ISBN: 978-1-59259-851-9

  • eBook Packages: MedicineMedicine (R0)

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