TY - JOUR
T1 - β-Lapachone-induced apoptosis in human prostate cancer cells
T2 - Involvement of NQO1/xip3
AU - Planchon, Sarah M.
AU - Pink, John J.
AU - Tagliarino, Colleen
AU - Bornmann, William G.
AU - Varnes, Marie E.
AU - Boothman, David A.
PY - 2001/7/1
Y1 - 2001/7/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Atypical PARP cleavage
KW - NQO1
KW - P53 cleavage
KW - Prostate cancer
KW - X-ray-inducible protein 3 (xip3)
KW - β-lapachone
UR - http://www.scopus.com/inward/record.url?scp=0035398693&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035398693&partnerID=8YFLogxK
U2 - 10.1006/excr.2001.5234
DO - 10.1006/excr.2001.5234
M3 - Article
C2 - 11412042
AN - SCOPUS:0035398693
SN - 0014-4827
VL - 267
SP - 95
EP - 106
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 1
ER -