TRAIL: a multifunctional cytokine

Schaefer, Uta; Voloshanenko, Oksana; Willen, Daniela; Walczak, Henning

doi:10.2741/2354

Cited by 114 publications

(130 citation statements)

References 76 publications

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“…Therefore, the development of new therapeutic strategies is necessary for the treatment of this type of cancer. The Apo2L/tumor necrosis factor (TNF)-a-related apoptosis-inducing ligand (TRAIL) is a relatively new member of the TNF family known to induce apoptosis in a variety of cancers (Schaefer et al, 2007). TRAIL can bind to five receptors, of which four are located at the cell surface: TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

et al. 2008

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To define novel pathways that regulate susceptibility to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in non-small cell lung cancer (NSCLC), we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant NSCLC cells, levels of different miRs are increased, and in particular, miR-221 and -222. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. Indeed, transfection with anti-miR-221 and -222 rendered CALU-1-resistant cells sensitive to TRAIL. Conversely, H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3 0 -UTR of Kit and p27 kip1 mRNAs, but interfere with TRAIL signaling mainly through p27 kip1 . In conclusion, we show that high expression levels of miR-221 and -222 are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets or diagnostic tool for TRAIL resistance in NSCLC.

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Section: Introductionmentioning

confidence: 99%

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

et al. 2008

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“…The discovery of TRAIL and detailed analysis of TRAIL-R1/R2-mediated death signaling in normal and cancer cells led to the theory that TRAIL-R-mediated pathway might be effective for the induction of apoptosis [39,40]. One important advantage of TRAIL, compared to TNFα and FasL, is its relatively low toxicity in vivo [41]. The safety and efficacy of soluble TRAIL and anti-TRAIL-R1/R2 agonistic mAbs combined with chemotherapy are currently undergoing evaluation in several clinical trials [41].…”

Section: Discussionmentioning

confidence: 99%

“…One important advantage of TRAIL, compared to TNFα and FasL, is its relatively low toxicity in vivo [41]. The safety and efficacy of soluble TRAIL and anti-TRAIL-R1/R2 agonistic mAbs combined with chemotherapy are currently undergoing evaluation in several clinical trials [41]. Unfortunately, sensitivity to TRAIL is not a universal feature of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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“…However, cytotoxic chemotherapy and ionizing radiation not only affect tumors, but also normal cells, especially dividing lymphocytes that are required to develop an antitumor immune response. In contrast to these conventional therapies, TRAIL, via interaction with the correspondent TRAIL-R1 and TRAIL-R2 on surface of cancer cells, may induce a fatal signaling cascade in cancer cells and have only minimal cytotoxic effects in normal cells [7,8]. Unfortunately, most human melanomas are resistant to TRAIL [38].…”

Section: Discussionmentioning

confidence: 99%

“…Examples of this strategy include the use of recombinant death ligands of the TNF superfamily, such as Fas Ligand and TRAIL, or the correspondent agonistic monoclonal antibodies to the death receptors, Fas, TRAIL-R1/DR4 or TRAIL-R2/DR5 [5,6]. Targeting TRAIL-receptor mediated signaling pathways for induction of apoptosis is currently under evaluation in multiple clinical trials for several types of cancer [7,8]. Finally, combined modality treatments, which include γ-irradiation and specific inhibitions of the cell survival pathways, appear to be promising approaches for the control and suppression of cancer development [9,10].…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival

2008

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The incidence of melanoma continues to dramatically increase in most Western countries with predominantly Caucasian populations. However, only limited therapies for the metastatic stage of the disease are currently available. The main purpose of this study is to determine approaches that can substantially increase radiosensitivity of melanoma cells. The PI3K-AKT, NF-κB and COX-2 pathways, which are involved in the radioprotective response, are highly active in melanoma cells. Pharmacological suppression of COX-2 and PI3K-AKT, or RNAi-mediated knockdown of COX-2, substantially increased levels of G2/M arrest of the cell cycle and decreased clonogenic survival of gamma-irradiated melanomas, predominantly via a necrotic mechanism. On the other hand, resveratrol, a polyphenolic phytoalexin, selectively targets numerous cell signaling pathways, decreasing clonogenic survival primarily via an apoptotic mechanism. In melanoma cells, resveratrol inhibits STAT3 and NF-κB-dependent transcription, culminating in suppression of cFLIP and Bcl-xL expression, while activating the MAPK-and the ATM-Chk2-p53 pathways. Resveratrol also upregulates TRAIL promoter activity and induces TRAIL surface expression in some melanoma cell lines, resulting in a rapid development of apoptosis. Sequential treatment of melanoma cells, first with γ-irradiation to upregulate TRAIL-R surface expression, and then with resveratrol to suppress antiapoptotic proteins cFLIP and Bcl-xL and induce TRAIL surface expression, had dramatic effects on upregulation of apoptosis in some melanoma lines, including SW1 and WM35. However, for melanoma lines exhibiting suppressed translocation of TRAIL to the cell surface, a necrotic mechanism of cell death was primarily involved in radiation response. Hence, surface expression of TRAIL induced by resveratrol appears to be a decisive event, one HHS Public Access

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TRAIL: a multifunctional cytokine

Cited by 114 publications

References 76 publications

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival

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