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Methoxychalcone induces cell‐cycle arrest and apoptosis in human hormone‐resistant prostate cancer cells through PI 3‐kinase‐independent inhibition of mTOR pathways
Author(s) -
Sun YuWei,
Huang WeiJan,
Hsiao CheJen,
Chen YiCheng,
Lu PinHsuan,
Guh JihHwa
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21165
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , cell cycle , biology , cancer research , microbiology and biotechnology , cyclin dependent kinase , cyclin d1 , cyclin b , rptor , g1 phase , cell growth , cyclin d , clonogenic assay , cell cycle checkpoint , signal transduction , apoptosis , biochemistry
BACKGROUND Chalcones are contained in fruits and vegetables, and have been suggested to display anticancer activities. In this study, the anticancer mechanism of WJ9708011 (a methoxychalcone derivative) was delineated in human prostate cancer cells. METHOD Cell proliferation was examined by sulforhodamine B and clonogenic assays. Cell‐cycle progression and mitochondrial membrane potential (ΔΨ m ) were detected by flow cytometric analysis. Expressions of protein and mRNA were detected by Western blot and RT‐PCR technique, respectively. The protein synthesis was examined by [ 3 H]leucine incorporation assay. The overexpression or knockdown techniques for specific target protein were also used in this study. RESULTS WJ9708011 induced time‐ and concentration‐dependent G1 arrest of the cell cycle and subsequent apoptosis in human prostate cancer cells. The G1‐arrest effect was confirmed by down‐regulated expressions of several G1‐phase regulators, including cyclin D1, cyclin E, cyclin‐dependent kinase (Cdk)‐4, Cdk2, phospho‐RB, E2F‐1, and Cdc25A. The mRNA expressions of cyclin D1 and cyclin E were also inhibited through the suppression of NF‐κB. WJ9708011 blocked the protein synthesis and inhibited mammalian target of rapamycin (mTOR) signaling pathways. The suppression of mTOR pathways were irrespective of Akt‐ and AMPK‐activated protein kinase (AMPK), but were attributed to mitochondrial stress, in which the down‐regulation of survivin protein level may play a crucial role. CONCLUSIONS The data suggest that WJ9708011 induces transcriptional and translational suppression of cell‐cycle regulators that might be through Akt‐ and AMPK‐independent loss of ΔΨ m and inhibition of mTOR signaling pathway, leading to G1 arrest of the cell cycle and subsequent apoptotic cell death. Prostate 70:1295–1306, 2010. © 2010 Wiley‐Liss, Inc.