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Title: Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Abstract

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-{kappa}B that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. 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-{kappa}B 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 {gamma}-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by {gamma}-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 surfacemore » 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.« less

Authors:
 [1];  [2];  [3];  [1];  [1]
  1. Center for Radiological Research, Columbia University, New York, NY 10032 (United States)
  2. Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States)
  3. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032 (United States)
Publication Date:
OSTI Identifier:
21045954
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 314; Journal Issue: 5; Other Information: DOI: 10.1016/j.yexcr.2007.12.012; PII: S0014-4827(07)00586-1; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALDEHYDES; APOPTOSIS; BORON CHLORIDES; FLUORESCENCE; GAMMA RADIATION; MELANOMAS; MITOCHONDRIA; RECEPTORS; TRANSCRIPTION FACTORS

Citation Formats

Ivanov, Vladimir N., Partridge, Michael A, Johnson, Geoffrey E, Huang, Sarah X.L., Zhou, Hongning, Hei, Tom K, and Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032. Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. United States: N. p., 2008. Web. doi:10.1016/j.yexcr.2007.12.012.
Ivanov, Vladimir N., Partridge, Michael A, Johnson, Geoffrey E, Huang, Sarah X.L., Zhou, Hongning, Hei, Tom K, & Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032. Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. United States. https://doi.org/10.1016/j.yexcr.2007.12.012
Ivanov, Vladimir N., Partridge, Michael A, Johnson, Geoffrey E, Huang, Sarah X.L., Zhou, Hongning, Hei, Tom K, and Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032. 2008. "Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression". United States. https://doi.org/10.1016/j.yexcr.2007.12.012.
@article{osti_21045954,
title = {Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression},
author = {Ivanov, Vladimir N. and Partridge, Michael A and Johnson, Geoffrey E and Huang, Sarah X.L. and Zhou, Hongning and Hei, Tom K and Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032},
abstractNote = {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-{kappa}B that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. 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-{kappa}B 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 {gamma}-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by {gamma}-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.},
doi = {10.1016/j.yexcr.2007.12.012},
url = {https://www.osti.gov/biblio/21045954}, journal = {Experimental Cell Research},
issn = {0014-4827},
number = 5,
volume = 314,
place = {United States},
year = {Mon Mar 10 00:00:00 EDT 2008},
month = {Mon Mar 10 00:00:00 EDT 2008}
}