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Molecular Pharmacology

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Research ArticleArticle

Aspirin Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-Regulation

Jinsang Yoo and Yong J. Lee
Molecular Pharmacology December 2007, 72 (6) 1586-1592; DOI: https://doi.org/10.1124/mol.107.039610
Jinsang Yoo
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Yong J. Lee
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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity. TRAIL is known to induce apoptosis in cancer cells but spare most normal cells. In this study, we examined whether acetylsalicylic acid (ASA), so-called aspirin, enhances TRAIL-induced apoptosis in androgen-dependent LNCaP and androgen-independent LNCaP-derived prostate cancer cells. To evaluate the cell death effects of TRAIL in combination with ASA on tumor cells, we performed DNA fragmentation assay and immunoblot analysis for poly(ADP-ribose) polymerase-1, caspases, and anti-apoptotic proteins. We observed that ASA promoted TRAIL-induced apoptotic death in both LNCaP and its derived cells (C4, C4-2, and C4-2B). These enhancements of TRAIL's effect were related to the decrease in survivin protein expression by pretreatment with ASA. We also confirmed that knockdown in survivin expression by transfecting survivin small interfering RNA increased TRAIL-induced apoptosis. To study the mechanism of survivin down-regulation, we determined the levels of mRNA and the activities of survivin promoter in the ASA-treated and untreated cells. Reduction of the intracellular levels of survivin protein was due to a decrease in transcriptional activity. Data from electrophoretic mobility shift assay and chromatin immunoprecipitation analyses revealed that ASA inhibited the transcription factor E2F-1 binding activity to the survivin promoter region, which is known to regulate survivin gene transcription. Taken together, our studies suggested that ASA-promoted TRAIL cytotoxicity is mediated by down-regulating survivin, and the down-regulation of survivin is due to inhibition of E2F-1 binding activity to the survivin promoter region.

Footnotes

  • This work was supported by National Cancer Institute grants CA95191, CA96989, and CA121395; Department of Defense prostate program funds (PC020530 and PC040833), and Susan G. Komen Breast Cancer Foundation fund (BCTR60306).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.039610.

  • ABBREVIATIONS: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; ASA, acetylsalicylic acid; IAP, inhibitor of apoptosis protein; PAGE, polyacrylamide gel electrophoresis; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; siRNA, small interfering RNA; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; Sp1, specific protein 1; NF-κB, nuclear factor-κB; DTT, dithiothreitol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

    • Received July 3, 2007.
    • Accepted September 11, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Aspirin Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-Regulation

Jinsang Yoo and Yong J. Lee
Molecular Pharmacology December 1, 2007, 72 (6) 1586-1592; DOI: https://doi.org/10.1124/mol.107.039610

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Research ArticleArticle

Aspirin Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-Regulation

Jinsang Yoo and Yong J. Lee
Molecular Pharmacology December 1, 2007, 72 (6) 1586-1592; DOI: https://doi.org/10.1124/mol.107.039610
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