title: Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage.
abstract: Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or γ-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy.
authors.affiliation: Department of Medicine, University of Illinois, Chicago, Illinois, United States of America.
authors.forename: Marianna
authors.initials: M
authors.lastname: Halasi
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Gartel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013234:Stem Cells
chemical_list: D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D048670:MAP Kinase Kinase 4