β-Lapachone-induced apoptosis in human prostate cancer cells: Involvement of NQO1/xip3

Sarah M. Planchon, John J. Pink, Colleen Tagliarino, William G. Bornmann, Marie E. Varnes, David A. Boothman

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

β-Lapachone (β-lap) induces apoptosis in various cancer cells, and its intracellular target has recently been elucidated in breast cancer cells. Here we show that NAD(P)H:quinone oxidoreductase (NQO1/xip3) expression in human prostate cancer cells is a key determinant for apoptosis and lethality after β-lap exposures. β-Lap-treated, NQO1-deficient LNCaP cells were significantly more resistant to apoptosis than NQO1-expressing DU-145 or PC-3 cells after drug exposures. Formation of an atypical 60-kDa PARP cleavage fragment in DU-145 or PC-3 cells was observed after 10 μM β-lap treatment and correlated with apoptosis. In contrast, LNCaP cells required 25 μM β-lap to induce similar responses. Atypical PARP cleavage in β-lap-treated cells was not affected by 100 μM zVAD-fmk; however, coadministration of dicoumarol, a specific inhibitor of NQO1, reduced β-lap-mediated cytotoxicity, apoptosis, and atypical PARP cleavage in NQO1-expressing cells. Dicoumarol did not affect the more β-lap-resistant LNCaP cells. Stable transfection of LNCaP cells with NQO1 increased their sensitivity to β-lap, enhancing apoptosis compared to parental LNCaP cells or vector-alone transfectants. Dicoumarol increased survival of β-lap-treated NQO1-expressing LNCaP transfectants. NQO1 activity, therefore, is a key determinant of β-lap-mediated apoptosis and cytotoxicity in prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalExperimental Cell Research
Volume267
Issue number1
DOIs
StatePublished - Jul 1 2001

Keywords

  • Apoptosis
  • Atypical PARP cleavage
  • NQO1
  • P53 cleavage
  • Prostate cancer
  • X-ray-inducible protein 3 (xip3)
  • β-lapachone

ASJC Scopus subject areas

  • Cell Biology

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