Inhibiting the expression of DNA replication-initiation proteins induces apoptosis in human cancer cells.
DNA replication-initiation proteins are expressed in cancer cells, whereas some of these proteins are not expressed in nonproliferating normal cells. Therefore, replication-initiation proteins may present attractive targets for anticancer therapy. Using selected antisense oligodeoxynucleotides and small interfering RNA molecules targeted to the mRNA encoding the DNA replication-initiation proteins hCdc6p, hMcm2p, and hCdc45p, we show that the target genes could be effectively and specifically silenced and that, consequently, DNA replication and cell proliferation were inhibited in cultured human cells. In addition, silencing of these genes resulted in apoptosis in both p53-positive and -negative cancer cells but not in normal cells: cancer cells entered an abortive S-phase, whereas normal cells arrested mainly in G(1) phase. Our studies are the first to suggest that inhibiting the expression of selective replication-initiation proteins is a novel and effective anticancer strategy.
Feng
Daorong
D
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Tu
Zheng
Z
Wu
Wenyan
W
Liang
Chun
C
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064111:Minichromosome Maintenance Complex Component 2; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
C113571:CDC45 protein, human; C103706:CDC6 protein, human; C491876:Cdc45 protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D064111:Minichromosome Maintenance Complex Component 2