Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy

Leithner, Katharina; Stacher, Elvira; Wurm, Robert; Ploner, Ferdinand; Quehenberger, Franz; Wohlkoenig, Christoph; Bálint, Zoltán; Polachova, Jana; Olschewski, Andrea; Samonigg, Hellmut; Popper, Helmut; Olschewski, Horst

doi:10.1016/j.lungcan.2008.10.015

Cited by 29 publications

(27 citation statements)

References 29 publications

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“…Previous reports have shown that DR5 localizes predominantly in the plasma membrane and in the trans-Golgi network in human melanoma cells (25), melanocytes, endothelial cells, and fibroblasts (26). Recently, DR5 was detected in the cytoplasm in the majority of tissue samples obtained from patients suffering from non-small cell lung carcinoma, and it was detected in the nucleus in 27% of the same samples (27). Our present observation of the nuclear localization of DR5 in HepG2 and HeLa cells is consistent with these clinical observations.…”

Section: Discussionmentioning

confidence: 97%

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Kojima

Nakayama

Nishina

et al. 2011

Journal of Biological Chemistry

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Background: Nuclear localization of DR5 was observed in TRAIL-resistant tumor cells in human. Results: TRAIL-resistant tumor cells were sensitized to TRAIL by knockdown of importin ␤1. Conclusion: Importin ␤1-mediated nuclear translocation of DR5 limits DR5/TRAIL-induced cell death of human tumor cells.Significance: This provides a novel strategy to improve the efficiency of recombinant TRAIL and anti-DR5 antibodies in cancer therapy.

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Section: Discussionmentioning

confidence: 97%

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Kojima

Nakayama

Nishina

et al. 2011

Journal of Biological Chemistry

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“…The mislocalization of DR4 and DR5 has been observed in other cell types, including CD4+ T cells (27) and cells of cervical neoplasia (28), melanoma (29), and non-small cell lung cancer (NSCLC) (30,31). In these cases, both DR4 and DR5 were reported to be mainly expressed in cytoplasm and/or nucleus.…”

Section: Discussionmentioning

confidence: 99%

Mislocalization of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells

et al. 2012

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ABSTRACT:Multiple clinical trials are ongoing to evaluate the potential antitumor activity of human TNF variants, Fas ligand (FasL), TNF-related apoptosis inducing ligand (TRAIL) and its agonistic antibodies. These drug products act through the death receptors (DRs) TNF receptor 1 (TNFR1), Fas/CD95, DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2), respectively. Therefore, characterization of the level and localization of DR expression in cancer cells is important for DR-targeted therapy. In this study, we examined the subcellular distribution of the four DRs in a panel of 10 human breast cancer cell lines by western blots and flow cytometry and 50 human breast tumors by immunohistochemistry. Despite their total protein expressions, the DRs were found to be absent on the surface of some cell lines. Consistent with this result, all four DRs were found to be mostly expressed in the cytoplasm and/or the nucleus of primary breast tumors (n=50). We further determined the growth inhibition activity (GI50) of the death ligands, recombinant human TNFα, FasL and TRAIL, and found a correlation with the subcellular localization of the corresponding DRs. These results demonstrate an aberrant expression of the death receptors in breast cancer cells, and suggest that the lack of surface DRs appears to be predictive of tumor resistance to DR-targeted therapies.

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“…In NSCLC for example, DR expression has been shown in most paraffin-embedded primary tumor samples (55). However, recent reports suggest that this signal is located predominately in the cytoplasm and not the cell membrane (56). In a recent report of 2 study of mapatumumab with paclitaxel/carboplatin in patients with solid tumors including NSCLC, the majority of patient tumor samples were negative for membranous DR4 by immunohistochemistry (42).…”

Section: Translational Implicationsmentioning

confidence: 99%

Death Receptor Agonists as a Targeted Therapy for Cancer

Wiezorek

Holland

Graves

2010

Clinical Cancer Research

156

129

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Apoptosis is integral to normal, physiologic processes that regulate cell number and results in the removal of unnecessary or damaged cells. Apoptosis is frequently dysregulated in human cancers, and recent advancements in our understanding of the regulation of programmed cell death pathways has led to the development of novel agents to reactivate apoptosis in malignant cells. The activation of cell surface death receptors by tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5. Many of these agents are currently being evaluated in phase 1 or 2 trials, either as a single agent or in combination with cytotoxic chemotherapy or other targeted agents. The opportunities and challenges associated with the development of death receptor agonists as cancer therapeutics, the status of ongoing clinical evaluations, and the progress toward identifying predictive biomarkers for patient selection and pharmacodynamic markers of response are reviewed.

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Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy

Cited by 29 publications

References 29 publications

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Mislocalization of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells

Death Receptor Agonists as a Targeted Therapy for Cancer

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