title: Chemoprevention with protein kinase A RIalpha antisense in DMBA-mammary carcinogenesis.
abstract: Cancer is potentially preventable disease. A surprising variety of intracellular pathways can be a target for chemoprevention. Earlier it was discovered that cAMP-mediated system can play important role in prevention of DMBA-mammary carcinogenesis. There are two types of cAMP-dependent protein kinases (PKA), type I (PKA-I) and type II (PKA-II), which share a common catalytic (C) subunits, but contain distinct regulatory (R) ones, RI versus RII, respectively. Evidence suggests that increased expression of PKA-I and its regulatory subunit (RIalpha) correlates with tumorogenesis and tumor growth. It was found that downregulation of RIalpha by 21-mer antisense oligonucleotide led to growth arrest of cancer cells. The effect of RIalpha antisense oligonucleotide correlated with a decrease in RIalpha protein and a concomitant increase in RIIbeta protein level. It was shown that antisense RIalpha can protect in a sequence-specific manner from 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis. At 90 days after DMBA intubation, RIalpha-antisense-treated rats exhibited significantly lower number of tumors per rat, than untreated control animals. The antisense also delayed the first tumor appearance. An increase in RIalpha and PKA-I levels in the mammary gland and liver preceded tumor production, and antisense downregulation of RIalpha restored normal levels of PKA-I and PKA-II in these tissues. Antisense RIalpha in the liver induced the phase II enzymes, glutathione S-transferase and quinone oxidoreductase, c-fos protein, and activator protein-1 (AP-1)- and cAMP response element (CRE)-directed transcription. In the mammary gland, antisense RIalpha promoted DNA repair processes. In contrast, the CRE transcription-factor decoy could not mimic these effects of antisense RIalpha. The results demonstrate that RIalpha antisense produces dual anticarcinogenic effects : (a) increasing DMBA detoxification in the liver by increasing phase II enzyme activities, increasing CRE-binding-protein phosphorylation and enhancing CRE- and AP-1 directed transcription; and (b) activating DNA repair processes in the mammary gland by downregulating of PKA-1.
authors.affiliation: Cellular Biochemistry Section, Basic Research Laboratory, CCR, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Nesterova
authors.forename: Yoon S
authors.initials: YS
authors.lastname: Cho-Chung
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents; D002273:Carcinogens; D000242:Cyclic AMP / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D015536:Down-Regulation; D006801:Humans; D008321:Mammary Glands, Animal; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016376:Oligonucleotides, Antisense; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; C517836:Prkar1a protein, rat; D014157:Transcription Factors; D015127:9,10-Dimethyl-1,2-benzanthracene; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases