Direct Repression of <i>FLIP</i> Expression by c-myc Is a Major Determinant of TRAIL Sensitivity

Ricci, M.; Jin, Zhaoyu; Dews, Michael; Yu, Duonan; Thomas-Tikhonenko, Andrei; Dicker, David T.; El‐Deiry, Wafik S.

doi:10.1128/mcb.24.19.8541-8555.2004

Cited by 228 publications

(209 citation statements)

References 65 publications

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“…Additional reporter constructs used included: 1.5 kb TRAIL-promoter-Luc [22], 1 kb cFLIP-promoter-Luc [23,24] and p53RE-Luc [25]. Transient transfection of different reporter constructs (1 μg) together with pCMV-βgal (0.25μg) into 5×10 5 melanoma cells was performed using Lipofectamine (Life Technologies-Invitrogen).…”

Section: Transfection and Luciferase Assaymentioning

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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Section: Transfection and Luciferase Assaymentioning

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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“…Additional reporter constructs used included: 1.5 kb TRAILpr-Luc [26], 1.8 kb TRAIL-R1pr-Luc [27], 1 kb cFLIPpr-Luc [28,29]. Transient transfection of different reporter constructs (1 μg) together with pCMV-βgal (0.25μg) into 5×10 5 melanoma cells was performed using Lipofectamine (Life Technologies-Invitrogen).…”

Section: Transfection and Luciferase Assaymentioning

confidence: 99%

“…3E, D and 4B, D). In order to more precisely characterize the regulation of cFLIP/CFLAR expression, we used reporter constructs containing the human cFLIP promoter [28,29]. In an addition to previously described ciselements, such as SP1-and cMyc-binding sites, this promoter contains four putative AP1-binding sites, one putative CRE site and two GAS sites that could bind STAT3, but no NF-κB binding sites (Fig.…”

Section: Regulation Of the Cflip Promoter Activity And Cflip Expressimentioning

confidence: 99%

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Ivanov

Hei

2006

Experimental Cell Research

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AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio-and chemotherapy. In the present study we observed strong effects of sodium arsenite treatment on upregulation of TRAILmediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL-and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via down-regulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anti-cancer treatment.

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“…TRAIL sensitivity has been correlated with levels or localization of various proteins, including Akt, FLIP and c-myc (33,34). Several investigators demonstrated increased activity of TRAIL-based therapies in combination with alkylating agents clinically used to treat malignant gliomas.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Glioma Radiotherapy and Chemotherapy Response With Targeted Antibody Therapy Against Death Receptor 5

Fiveash

Gillespie

Oliver

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-TRA-8 is an agonistic mouse monoclonal antibody that binds to TRAIL death receptor 5 (DR5) which induces apoptosis in cancer cells through a caspase-8 dependent mechanism. We investigated the ability of TRA-8 to augment radiation therapy (RT) and chemotherapy response of human glioma cells in vitro and in vivo.Methods and Materials-In vitro cytotoxicity of TRA-8 and temozolomide (Tmz) or RT was examined using ATP dependent viability and clonogenic survival assays with 5 glioma cell lines. DR5 expression was determined by flow cytometry. In vivo studies included subcutaneous and intracranial xenograft models testing various combination treatments, including RT, Tmz, and TRA-8.Results-TRA-8 combined with Tmz or RT produced enhanced cytotoxicity against 5 glioma cell lines compared to individual agents. DR5 upregulation occurred in response to RT. Complete tumor regressions in subcutaneous experiments were most common in animals that received combination therapy with TRA-8/Tmz/RT. TRA-8 enhanced tumor growth delay in combination with RT or Tmz. TRA-8 alone had limited activity against intracranial tumors, whereas median survival of mice treated with TRA-8/Tmz/RT was significantly greater than control or TRA-8 alone treated mice. Median survival of mice treated with TRA-8/Tmz/RT or chemoradiation only was significantly greater than control or TRA-8 treated mice. A trend towards improved survival was observed comparing TRA-8/ Tmz/RT treated animals vs. Tmz/RT.Conclusions-These preliminary findings support the hypothesis that TRA-8 will augment RT and chemotherapy response in gliomas. A humanized version of TRA-8 is being evaluated in a Phase II clinical trial.

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Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity

Abstract: Tumor necrosis factor alpha (TNF-␣)-related apoptosis-inducing ligand (TRAIL) is

Cited by 228 publications

References 65 publications

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

Enhancement of Glioma Radiotherapy and Chemotherapy Response With Targeted Antibody Therapy Against Death Receptor 5

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