Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1

Ji Hoon Jang, Tae Jin Lee, Eun Sun Yang, Do Sik Min, Young Ho Kim, Sang Hyun Kim, Yung Hyun Choi, Jong Wook Park, Kyeong Sook Choi, Taeg Kyu Kwon

Research output: Contribution to journalArticle

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Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. Compound C, a cell-permeable pyrrazolopyrimidine derivative, acts as a potent, selective, reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). In this study, we show that compound C sensitizes Caki human renal cancer cells, but not normal human skin fibroblast cells (HSF) and human mesangial cells, to TRAIL-mediated apoptosis. However, AMPK siRNA failed to affect TRAIL-mediated apoptosis in Caki cells and transduction of dominant negative AMPK rather attenuated TRAIL-induced apoptosis, indicating that the effect of compound C on sensitization of TRAIL-induced apoptosis is independent of AMPK activity. Interestingly, we found that down-regulation of c-FLIPL and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIPL and Mcl-1 were caused by the decreased protein stability of c-FLIPL and Mcl-1, but not by their transcriptional control, in compound C-treated cells. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with compound C and TRAIL as well as recovered the expression levels of c-FLIPL and Mcl-1 down-regulated by the combinatory treatment with compound C plus TRAIL, suggesting that compound C-stimulated TRAIL-induced apoptosis appears to be dependent on the generation of reactive oxygen species for down-regulation of c-FLIPL and Mcl-1. Taken together, the present study demonstrates that compound C enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIPL and Mcl-1 down-regulation.

Original languageEnglish
Pages (from-to)2194-2203
Number of pages10
JournalExperimental Cell Research
Volume316
Issue number13
DOIs
Publication statusPublished - 2010 Aug

Fingerprint

Renal Cell Carcinoma
Reactive Oxygen Species
Down-Regulation
Apoptosis
AMP-Activated Protein Kinases
Mesangial Cells
Protein Stability
Small Interfering RNA
Cysteine
Cell Death
Tumor Necrosis Factor-alpha
Fibroblasts
Adenosine Triphosphate
Ligands
Skin
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Jang, Ji Hoon ; Lee, Tae Jin ; Yang, Eun Sun ; Min, Do Sik ; Kim, Young Ho ; Kim, Sang Hyun ; Choi, Yung Hyun ; Park, Jong Wook ; Choi, Kyeong Sook ; Kwon, Taeg Kyu. / Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1. In: Experimental Cell Research. 2010 ; Vol. 316, No. 13. pp. 2194-2203.
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abstract = "The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. Compound C, a cell-permeable pyrrazolopyrimidine derivative, acts as a potent, selective, reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). In this study, we show that compound C sensitizes Caki human renal cancer cells, but not normal human skin fibroblast cells (HSF) and human mesangial cells, to TRAIL-mediated apoptosis. However, AMPK siRNA failed to affect TRAIL-mediated apoptosis in Caki cells and transduction of dominant negative AMPK rather attenuated TRAIL-induced apoptosis, indicating that the effect of compound C on sensitization of TRAIL-induced apoptosis is independent of AMPK activity. Interestingly, we found that down-regulation of c-FLIPL and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIPL and Mcl-1 were caused by the decreased protein stability of c-FLIPL and Mcl-1, but not by their transcriptional control, in compound C-treated cells. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with compound C and TRAIL as well as recovered the expression levels of c-FLIPL and Mcl-1 down-regulated by the combinatory treatment with compound C plus TRAIL, suggesting that compound C-stimulated TRAIL-induced apoptosis appears to be dependent on the generation of reactive oxygen species for down-regulation of c-FLIPL and Mcl-1. Taken together, the present study demonstrates that compound C enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIPL and Mcl-1 down-regulation.",
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Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1. / Jang, Ji Hoon; Lee, Tae Jin; Yang, Eun Sun; Min, Do Sik; Kim, Young Ho; Kim, Sang Hyun; Choi, Yung Hyun; Park, Jong Wook; Choi, Kyeong Sook; Kwon, Taeg Kyu.

In: Experimental Cell Research, Vol. 316, No. 13, 08.2010, p. 2194-2203.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1

AU - Jang, Ji Hoon

AU - Lee, Tae Jin

AU - Yang, Eun Sun

AU - Min, Do Sik

AU - Kim, Young Ho

AU - Kim, Sang Hyun

AU - Choi, Yung Hyun

AU - Park, Jong Wook

AU - Choi, Kyeong Sook

AU - Kwon, Taeg Kyu

PY - 2010/8

Y1 - 2010/8

N2 - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. Compound C, a cell-permeable pyrrazolopyrimidine derivative, acts as a potent, selective, reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). In this study, we show that compound C sensitizes Caki human renal cancer cells, but not normal human skin fibroblast cells (HSF) and human mesangial cells, to TRAIL-mediated apoptosis. However, AMPK siRNA failed to affect TRAIL-mediated apoptosis in Caki cells and transduction of dominant negative AMPK rather attenuated TRAIL-induced apoptosis, indicating that the effect of compound C on sensitization of TRAIL-induced apoptosis is independent of AMPK activity. Interestingly, we found that down-regulation of c-FLIPL and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIPL and Mcl-1 were caused by the decreased protein stability of c-FLIPL and Mcl-1, but not by their transcriptional control, in compound C-treated cells. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with compound C and TRAIL as well as recovered the expression levels of c-FLIPL and Mcl-1 down-regulated by the combinatory treatment with compound C plus TRAIL, suggesting that compound C-stimulated TRAIL-induced apoptosis appears to be dependent on the generation of reactive oxygen species for down-regulation of c-FLIPL and Mcl-1. Taken together, the present study demonstrates that compound C enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIPL and Mcl-1 down-regulation.

AB - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. Compound C, a cell-permeable pyrrazolopyrimidine derivative, acts as a potent, selective, reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). In this study, we show that compound C sensitizes Caki human renal cancer cells, but not normal human skin fibroblast cells (HSF) and human mesangial cells, to TRAIL-mediated apoptosis. However, AMPK siRNA failed to affect TRAIL-mediated apoptosis in Caki cells and transduction of dominant negative AMPK rather attenuated TRAIL-induced apoptosis, indicating that the effect of compound C on sensitization of TRAIL-induced apoptosis is independent of AMPK activity. Interestingly, we found that down-regulation of c-FLIPL and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIPL and Mcl-1 were caused by the decreased protein stability of c-FLIPL and Mcl-1, but not by their transcriptional control, in compound C-treated cells. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with compound C and TRAIL as well as recovered the expression levels of c-FLIPL and Mcl-1 down-regulated by the combinatory treatment with compound C plus TRAIL, suggesting that compound C-stimulated TRAIL-induced apoptosis appears to be dependent on the generation of reactive oxygen species for down-regulation of c-FLIPL and Mcl-1. Taken together, the present study demonstrates that compound C enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIPL and Mcl-1 down-regulation.

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