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Chemoprevention with Protein Kinase A RIα Antisense in DMBA‐Mammary Carcinogenesis
Author(s) -
NESTEROVA MARIA V.,
CHOCHUNG YOON S.
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1359.038
Subject(s) - dmba , carcinogenesis , downregulation and upregulation , protein kinase a , biology , kinase , microbiology and biotechnology , sense (electronics) , mammary tumor , cancer research , chemistry , endocrinology , cancer , biochemistry , gene , breast cancer , genetics
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 (RIα) correlates with tumorogenesis and tumor growth. It was found that downregulation of RIα by 21‐mer antisense oligonucleotide led to growth arrest of cancer cells. The effect of RIα antisense oligonucleotide correlated with a decrease in RIα protein and a concomitant increase in RIIβ protein level. It was shown that antisense RIα can protect in a sequence‐specific manner from 7,12‐dimethylbenz (a) anthracene (DMBA)‐induced mammary carcinogenesis. At 90 days after DMBA intubation, RIα‐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 RIα and PKA‐I levels in the mammary gland and liver preceded tumor production, and antisense downregulation of RIα restored normal levels of PKA‐I and PKA‐II in these tissues. Antisense RIα 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 RIα promoted DNA repair processes. In contrast, the CRE transcription‐factor decoy could not mimic these effects of antisense RIα. The results demonstrate that RIα 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.