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KMID : 0613820120220101277
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Journal of Life Science
2012 Volume.22 No. 10 p.1277 ~ p.1285
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Inhibition of SIRT1 Sensitizes TRAIL-Resistant MCF-7 Cells by Upregulation of DR5 and Inhibition of c-FLIP
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Lee Su-Hoon
Kim Hak-Bng
Kim Mi-Ju
Lee Jae-Won
Bae Jae-Ho
Kim Dong-Wan
Kang Chi-Dug
Kim Sun-Hee
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Abstract
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The tumor necrosis, factor-related, apoptosis-inducing ligand (TRAIL) is regarded as a potentially useful anticancer agent with excellent selectivity for cancer cells. However, a considerable number of cancer cells are resistant to apoptosis induction by TRAIL. Developing strategies to overcome this resistance are important for the successful use of TRAIL for cancer therapy. Here, we revealed that siRNA-mediated downregulation of SIRT1 or SIRT1 inhibitor Amurensin G upregulated DR5 and c-Myc and downregulated c-FLIP_{L/S} and Mcl-1, which was associated with sensitization of TRAIL-resistant MCF-7 cells to TRAIL. This result was followed by the activation of caspases, PARP cleavage, and downregulation of Bcl-2 in both TRAIL-treated MCF-7 cells transfected with SIRT1 siRNA and cells co-treated with Amurensin G and TRAIL. Our results suggest that the induction of DR5 and downregulation of c-FLIP via suppression of SIRT1 expression may be a useful strategy to increase the susceptibility of TRAIL-resistant cancer cells to TRAIL-induced cell death.
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KEYWORD
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), SIRT1, c-FLIP, MCF-7 cells, DR5
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