Antisense DNAs as multisite genomic modulators identified by DNA microarray.
Antisense oligodeoxynucleotides can selectively block disease-causing genes, and cancer genes have been chosen as potential targets for antisense drugs to treat cancer. However, nonspecific side effects have clouded the true antisense mechanism of action and hampered clinical development of antisense therapeutics. Using DNA microarrays, we have conducted a systematic characterization of gene expression in cells exposed to antisense, either exogenously or endogenously. Here, we show that in a sequence-specific manner, antisense targeted to protein kinase A RIalpha alters expression of the clusters of coordinately expressed genes at a specific stage of cell growth, differentiation, and activation. The genes that define the proliferation-transformation signature are down-regulated, whereas those that define the differentiation-reverse transformation signature are up-regulated in antisense-treated cancer cells and tumors, but not in host livers. In this differentiation signature, the genes showing the highest induction include genes for the G proteins Rap1 and Cdc42. The expression signature induced by the exogenously supplied antisense oligodeoxynucleotide overlaps strikingly with that induced by endogenous antisense gene overexpression. Defining antisense DNAs on the basis of their effects on global gene expression can lead to identification of clinically relevant antisense therapeutics and can identify which molecular and cellular events might be important in complex biological processes, such as cell growth and differentiation.
Cho
Y S
YS
Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1750, USA.
Kim
M K
MK
Cheadle
C
C
Neary
C
C
Becker
K G
KG
Cho-Chung
Y S
YS
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D016373:DNA, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D018076:DNA, Complementary / Q000235:genetics; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013873:Thionucleotides / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D021122:Protein Subunits; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013873:Thionucleotides; D017868:Cyclic AMP-Dependent Protein Kinases