Abstract
Expression of the RIalpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RIalpha gene expression on ovarian cancer cell growth. We report that RIalpha antisense treatment results in a reduction in RIalpha expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIalpha leads to blockade of both the serine-threonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.
MeSH terms
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Apoptosis
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Division / drug effects
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Cell Size
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Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
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Cyclic AMP-Dependent Protein Kinases / chemistry
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Cyclic AMP-Dependent Protein Kinases / genetics*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Down-Regulation
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Enzyme Activation / drug effects
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Humans
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Isoenzymes / chemistry
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Oligonucleotides, Antisense / chemistry
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Oligonucleotides, Antisense / pharmacology*
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3
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Signal Transduction* / drug effects
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Transfection
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Tumor Cells, Cultured
Substances
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Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
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Isoenzymes
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Oligonucleotides, Antisense
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PRKAR1A protein, human
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Proto-Oncogene Proteins
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RNA, Messenger
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Epidermal Growth Factor
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ErbB Receptors
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Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Receptor, ErbB-3
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Cyclic AMP-Dependent Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases