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Expression and Regulation of Death Receptors in Multiple Myeloma and Prostate Carcinoma

  • Chapter
Death Receptors in Cancer Therapy

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

Abstract

Several members of the tumor necrosis factor (TNF) gene superfamily induce apoptosis through engagement of their cognate death receptors (TNFR). To explore how their expression may be regulated, we used oligonucleotide arrays to determine TNFR gene expression using as a model multiple myeloma and prostate cancer cell lines. Expression levels for BCMA, HVEM, CD40, CD30, TACI, TNFR2, and Fas were considerably higher in multiple myeloma, pointing to their role in B-cell biology. Treatment with ionizing radiation led to increased levels of Fas, death receptor (DR)5, to a lesser extent decoy receptor (DcR)1 and DcR2, as well as BCMA, RANK, and ILA. Treatment with the topoisomerase I inhibitor CPT-11 led to increased expression of Fas, RANK, and DcR2, but not of BCMA or ILA, indicating a different transcriptional “signature” for ionizing radiation and chemotherapeutics. This increased expression level following genotoxic stress was prevented or attenuated in prostate cancer cells stably expressing a dominant-negative p53 mutant. Of the TNF family members, one that has received much attention recently is Apo2L/TRAIL (Apo2 ligand or TNF-related apoptosis-inducing ligand). Apo2L/TRAIL is unusual compared to any other cytokine, as it interacts with a complex system of receptors: two pro-apoptotic death receptors (DR4, DR5) and three anti-apoptotic decoy receptors (DcR1, DcR2, and osteoprotegerin [OPG]). This protein has generated tremendous excitement as a potential tumor-specific cancer therapeutic because, as a stable soluble trimer, it selectively induces apoptosis in many transformed cells but not in normal cells. We found that its expression can also be modulated by therapeutic agents.

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Authors and Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, Cleveland, OH

    Subrata Ray PhD, John G. Hissong MD, PhD, Marcela Oancea & Alex Almasan PhD

  2. Department of Chemistry, Cleveland State University, Cleveland, OH

    Marcela Oancea

  3. Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH

    Alex Almasan PhD

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  1. Subrata Ray PhD
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  2. John G. Hissong MD, PhD
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  3. Marcela Oancea
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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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Ray, S., Hissong, J.G., Oancea, M., Almasan, A. (2005). Expression and Regulation of Death Receptors in Multiple Myeloma and Prostate Carcinoma. 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:281

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  • DOI: https://doi.org/10.1385/1-59259-851-X:281

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