Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase IIα

Ren Kuo Lin, Nai Zhou, Yi Lisa Lyu, Yuan Chin Tsai, Chang Hsien Lu, John Kerrigan, Yu Tsung Chen, Ziqiang Guan, Tao Shih Hsieh, Leroy F. Liu

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Studies in animal models have indicated that dietary isothiocyanates (ITCs) exhibit cancer preventive activities through carcinogen detoxification- dependent and -independent mechanisms. The carcinogen detoxification-independent mechanism of cancer prevention by ITCs has been attributed at least in part to their ability to induce apoptosis of transformed (initiated) cells (e.g. through suppression of IκB kinase and nuclear factor κB as well as other proposed mechanisms). In the current studies we show that ITC-induced apoptosis of oncogene-transformed cells involves thiol modification of DNA topoisomerase II (Top2) based on the following observations. 1) siRNA-mediated knockdown of Top2α in both SV40-transformed MEFs and Ras-transformed human mammary epithelial MCF-10A cells resulted in reduced ITC sensitivity. 2) ITCs, like some anticancer drugs and cancer-preventive dietary components, were shown to induce reversible Top2α cleavage complexes in vitro. 3) ITC-induced Top2α cleavage complexes were abolished by co-incubation with excess glutathione. In addition, proteomic analysis revealed that several cysteine residues on human Top2α were covalently modified by benzyl-ITC, suggesting that ITC-induced Top2α cleavage complexes may involve cysteine modification. Interestingly, consistent with the thiol modification mechanism for Top2α cleavage complex induction, the thiol-reactive selenocysteine, but not the nonthiol-reactive selenomethionine, was shown to induce Top2α cleavage complexes. In the aggregate, our results suggest that thiol modification of Top2α may contribute to apoptosis induction in transformed cells by ITCs.

Original languageEnglish
Pages (from-to)33591-33600
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number38
DOIs
Publication statusPublished - Sep 23 2011
Externally publishedYes

Fingerprint

Isothiocyanates
Type II DNA Topoisomerase
Sulfhydryl Compounds
Apoptosis
Detoxification
Carcinogens
Cysteine
Selenocysteine
Selenomethionine
Neoplasms
isothiocyanic acid
Oncogenes
Proteomics
Small Interfering RNA
Glutathione
Animals
Breast
Phosphotransferases
Animal Models

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase IIα. / Lin, Ren Kuo; Zhou, Nai; Lyu, Yi Lisa; Tsai, Yuan Chin; Lu, Chang Hsien; Kerrigan, John; Chen, Yu Tsung; Guan, Ziqiang; Hsieh, Tao Shih; Liu, Leroy F.

In: Journal of Biological Chemistry, Vol. 286, No. 38, 23.09.2011, p. 33591-33600.

Research output: Contribution to journalArticle

Lin, RK, Zhou, N, Lyu, YL, Tsai, YC, Lu, CH, Kerrigan, J, Chen, YT, Guan, Z, Hsieh, TS & Liu, LF 2011, 'Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase IIα', Journal of Biological Chemistry, vol. 286, no. 38, pp. 33591-33600. https://doi.org/10.1074/jbc.M111.258137
Lin, Ren Kuo ; Zhou, Nai ; Lyu, Yi Lisa ; Tsai, Yuan Chin ; Lu, Chang Hsien ; Kerrigan, John ; Chen, Yu Tsung ; Guan, Ziqiang ; Hsieh, Tao Shih ; Liu, Leroy F. / Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase IIα. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 38. pp. 33591-33600.
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AU - Lu, Chang Hsien

AU - Kerrigan, John

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AU - Guan, Ziqiang

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AU - Liu, Leroy F.

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