The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints.
Int J Cancer, 2014/4/15;134(8):1991-2002.
Neumann J[1], Boerries M, Köhler R, Giaisi M, Krammer PH, Busch H, Li-Weber M
Affiliations
PMID: 24150948DOI: 10.1002/ijc.28521
Impact factor: 7.316
Abstract
Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.
Keywords: ATM; ATR; Cdc25A; Chk1; Chk2; cell cycle
MeSH terms
Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Benzofurans; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Damage; HCT116 Cells; HT29 Cells; Hep G2 Cells; Humans; Jurkat Cells; Leukemia; MCF-7 Cells; Phosphorylation; Plant Extracts; Protein Biosynthesis; Protein Kinases; RNA Interference; RNA, Small Interfering; S Phase Cell Cycle Checkpoints; T-Lymphocytes; cdc25 Phosphatases
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