Honokiol induces calpain-mediated glucose-regulated protein-94 cleavage and apoptosis in human gastric cancer cells and reduces tumor growth
Journal
PLoS ONE
Journal Volume
2
Journal Issue
10
Date Issued
2007
Author(s)
Abstract
Background. Honokiol, a small molecular weight natural product, has been shown to possess potent anti-neoplastic and anti-angiogenic properties. Its molecular mechanisms and the ability of anti-gastric cancer remain unknown. It has been-shown that the anti-apoptotic function of the glucose-regulated proteins (GRPs) predicts that their induction in neoplastic cells can lead to cancer progression and drug resistance. We explored the effects of honokiol on the regulation of GRPs and apoptosis in human gastric cancer cells and tumor growth. Methodology and Principal Findings. Treatment of various human gastric cancer cells with honokiol led to the induction of GRP94 cleavage, but did not affect GRP78. Silencing of GRP94 by small interfering RNA (siRNA) could induce cell apoptosis. Treatment of cells with honokiol or chemotherapeutics agent etoposide enhanced the increase in apoptosis and GRP94 degradation. The calpain activity and calpain-II (m-calpain) protein (but not calpain-I (μ-calpain)) level could also be increased by honokiol. Honokiol-induced GRP94 down-regulation and apoptosis in gastric cancer cells could be reversed by siRNA targeting calpain-II and calpain inhibitors. Furthermore, the results of immunofluerescence staining and immunoprecipitation revealed a specific interaction of GRP94 with calpain-II in cells following honokiol treatment. We next observed that tumor GRP94 over-expression and tumor growth in BALB/c nude mice, which were inoculated with human gastric cancer cells MKN45, are markedly decreased by honokiol treatment. Conclusions and Significance. These results provide the first evidence that honokiol-induced calpain-II-mediated GRP94 cleavage causes human gastric cancer cell apoptosis. We further suggest that honokiol may be a possible therapeutic agent to improve clinical outcome of gastric cancer. ? 2007 Sheu et al.
SDGs
Other Subjects
calpain; calpain 2; calpastatin; etoposide; glucose regulated protein 78; glucose regulated protein 94; honokiol; small interfering RNA; antineoplastic agent; biphenyl derivative; calpain; endoplasmin; glucose; honokiol; lignan; membrane protein; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; Bagg albino mouse; cancer cell; cancer inhibition; controlled study; down regulation; gene silencing; human; human cell; immunofluorescence; immunoprecipitation; male; mouse; nonhuman; protein degradation; protein function; protein protein interaction; stomach cancer; animal; apoptosis; biological model; chemistry; kinetics; metabolism; stomach tumor; tumor cell line; Mus musculus; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Calpain; Cell Line, Tumor; Glucose; Humans; Kinetics; Lignans; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Models, Biological; Stomach Neoplasms
Type
journal article