title: 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.
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.
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Neumann
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000187:drug effects / Q000378:metabolism*; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D010936:Plant Extracts; D034741:RNA, Small Interfering; C107772:rocaglamide; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
keywords: ATM; ATR; Cdc25A; Chk1; Chk2; cell cycle