Involvement of endoplasmic reticulum stress and activation of MAP kinases in β-lapachone-induced human prostate cancer cell apoptosis
Journal
Histology and Histopathology
Journal Volume
23
Journal Issue
11
Pages
1299-1308
Date Issued
2008
Author(s)
Abstract
β-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 β-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 β-lapachone. βLapachone-induced DU145 cell apoptosis was dosedependent and accompanied by cleavage of procaspase12 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 β-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 βlapachone-treated cells. These findings show that βlapachone-induced ER stress and MAP kinase phosphorylation is a novel signaling pathway underlying the molecular mechanism of the anticancer effect of βlapachone.
SDGs
Other Subjects
beta lapachone; calcium; calpain; caspase 12; caspase 7; dicoumarol; glucose regulated protein 78; growth arrest and DNA damage inducible protein 153; mitogen activated protein kinase; mitogen activated protein kinase p38; stress activated protein kinase; antineoplastic agent; beta lapachone; beta-lapachone; calcium; calpain; caspase; chelating agent; enzyme inhibitor; mitogen activated protein kinase; naphthoquinone; NQO1 protein, human; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone); unclassified drug; antineoplastic activity; apoptosis; article; calcium cell level; cancer cell; concentration response; controlled study; endoplasmic reticulum stress; enzyme activation; enzyme inhibition; enzyme phosphorylation; human; human cell; prostate cancer; protein degradation; protein expression; protein induction; protein phosphorylation; signal transduction; cell survival; dose response; drug antagonism; drug effect; endoplasmic reticulum; enzymology; homeostasis; male; metabolism; pathology; phosphorylation; physiological stress; prostate tumor; time; tumor cell line; Antineoplastic Agents; Apoptosis; Calcium; Calpain; Caspases; Cell Line, Tumor; Cell Survival; Chelating Agents; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Enzyme Activation; Enzyme Inhibitors; Homeostasis; Humans; Male; Mitogen-Activated Protein Kinases; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Phosphorylation; Prostatic Neoplasms; Signal Transduction; Stress, Physiological; Time Factors
Type
journal article