The TRAIL Receptor‐Ligand System: Biochemistry of Apoptosis Induction, Therapeutic Potential for Cancer Treatment and Physiological Function

Walczak, Henning; Koschny, Ronald; Willen, Daniela; Schader, Manuela B.; Sykora, Jaromir; Ganten, Tom M.; Haas, Tobias

doi:10.1002/9783527619665.ch2

Cited by 6 publications

(13 citation statements)

References 268 publications

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“…TNF-related apoptosis-inducing ligand (TRAIL), a ligand of the tumor necrosis factor (TNF ) family, is of special interest for clinical development, since TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells [6]. Currently, there are several clinical trials underway testing the therapeutic potential and safety of TRAIL agonists as anticancer agents [7][8][9]. However, since resistance towards TRAIL has been reported in about 50% of tested tumor cell lines, TRAIL agonists may not be successful as single agents in the clinic [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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Triggering apoptosis, the cell's intrinsic death program, is a promising approach for cancer therapy. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of death inducing ligands, is of special interest for cancer therapy, since TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. However, since many cancers fail to undergo apoptosis in response to TRAIL treatment, TRAIL-based combination therapies have been developed for cancer-cell specific sensitization towards TRAIL. Chromatin remodelling plays an important role in gene regulation and aberrant architecture of the chromatin has been implicated in tumor formation and progression. In recent years, HDAC inhibitors (HDACI) that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis. Synergistic tumor cell death has been reported in a variety of human cancers using different HDACI together with TRAIL. Here, recent advances in the understanding of the molecular events that underlie the synergistic interaction of HDACI and TRAIL are discussed as well as how this knowledge can be translated into the design of cancer-selective novel therapeutics.

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Section: Introductionmentioning

confidence: 99%

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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“…However, the role of the TRAIL system in pathogenesis of HCC is not clear, and no study had yet assessed the relevance of TRAIL receptor expression as a prognostic marker in this tumor (10).…”

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confidence: 99%

Expression, Cellular Distribution, and Prognostic Relevance of TRAIL Receptors in Hepatocellular Carcinoma

Kriegl

Jung

Engel

et al. 2010

Clinical Cancer Research

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Purpose: After the advent of targeted therapies for hepatocellular carcinoma (HCC), much work is being done to provide a comprehensive description of the different signaling pathways contributing to cell survival and proliferation in this tumor. Apoptotic signaling mediated by tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) represents an important mechanism of tumor surveillance, but its importance in the development of HCC is not known. We thus investigated the cellular distribution and the prognostic importance of TRAIL receptors in HCC.Experimental Design: Immunohistochemical staining for TRAIL receptors was evaluated in HCC tissues and in matched surrounding nontumor tissues of 157 HCC patients treated with liver transplantation or partial hepatectomy. Survival was analyzed in 93 patients who underwent partial hepatectomy.Results: The fraction of HCC samples with positive membrane staining for TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) was 1.4-and 2.7-fold lower compared with that of hepatocytes from surrounding tissues (P = 0.01). Loss of either TRAIL-R1 or TRAIL-R2, as confirmed by a multivariate analysis, significantly worsened 5-year survival of HCC patients {survival, 27% versus 52% and 15% versus 43%; hazard ratio (HR), 2.3 [95% confidence interval (CI), 1.1-4.4] and 2.4 (95% CI, 1.1-5.2), respectively}. Loss of both TRAIL receptors further decreased survival of patients [HR, 5.72 (95% CI, 2.1-15.5) versus double-negative staining; P = 0.001], indicating an additive effect on survival of TRAIL-R1 and TRAIL-R2.Conclusions: This pilot study suggests that loss of TRAIL receptors is a frequent feature of HCCs and an independent predictor of survival in patients undergoing partial hepatectomy. Future therapeutic protocols are likely to profit from the characterization of their expression and cellular distribution.

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“…Concordantly, the review of clinical data suggests a correlation between loss of TRAIL sensitivity, dedifferentiation and size of tumours, poor prognosis as well as tumour recurrence (Walczak et al 2008). In numerous preclinical models, TRAIL has been shown to selectively induce apoptosis in cancer cells while sparing normal cells, suggesting its use in cancer therapy (Wiley et al 1995, Griffith et al 2009).…”

Section: Introductionmentioning

confidence: 92%

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

Zitzmann

Toni²,

Rüden³

et al. 2011

Endocrine Related Cancer

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The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro-and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP S , caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP S or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

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The TRAIL Receptor‐Ligand System: Biochemistry of Apoptosis Induction, Therapeutic Potential for Cancer Treatment and Physiological Function

Cited by 6 publications

References 268 publications

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Expression, Cellular Distribution, and Prognostic Relevance of TRAIL Receptors in Hepatocellular Carcinoma

The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells

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