Publication: Involvement of endoplasmic reticulum stress and activation of MAP kinases in B-lapachone-induced human prostate cancer cell apoptosis
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Date
2008
Authors
Lien, Yi-Chen ; Kung, Hsiu-Ni ; Lu, Kuo-Shyan ; Jeng, Chung-Jiuan ; Chau, Yat-Pang
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
ß-Lapachone, an o-naphthoquinone, induces
various carcinoma cells to undergo apoptosis, but the
mechanism is poorly understood. In the present study,
we found that the ß-lapachone-induced apoptosis of
DU145 human prostate carcinoma cells was associated
with endoplasmic reticulum (ER) stress, as shown by
increased intracellular calcium levels and induction of
GRP-78 and GADD-153 proteins, suggesting that the
endoplasmic reticulum is a target of ß-lapachone. ß-
Lapachone-induced DU145 cell apoptosis was dosedependent
and accompanied by cleavage of procaspase-
12 and phosphorylation of p38, ERK, and JNK, followed
by activation of the executioner caspases, caspase-7 and
calpain. However, pretreatment with the general caspase
inhibitor, z-VAD-FMK, or calpain inhibitors, including
ALLM or ALLN, failed to prevent ß-lapachone-induced
apoptotic cell death. Blocking the enzyme activity of
NQO1 with dicoumarol, a known NQO1 inhibitor, or
preventing an increase in intracellular calcium levels
using BAPTA-AM, an intracellular calcium chelator,
substantially inhibited MAPK phosphorylation, abolished the activation of calpain, caspase-12 and
caspase-7, and provided significant protection of ßlapachone-
treated cells. These findings show that ßlapachone-
induced ER stress and MAP kinase
phosphorylation is a novel signaling pathway underlying
the molecular mechanism of the anticancer effect of ßlapachone.
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