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Antisense Protein Kinase A RI Inhibits 7,12-Dimethylbenz(a)anthracene-Induction of Mammary Cancer

Blockade at the Initial Phase of Carcinogenesis

Cellular Biochemistry Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Purpose: There are two types of cyclic AMP (cAMP)-dependent protein kinase (PKA), type I (PKA-I) and type II (PKA-II), which share a common catalytic (C) subunit but contain distinct regulatory (R) subunits, RI versus RII, respectively. Evidence suggests that increased expression of PKA-I and its regulatory subunit (RI) correlates with tumorigenesis and tumor growth. We investigated the effect of sequence-specific inhibition of RI gene expression at the initial phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis.

Experimental Design: Antisense RI oligodeoxynucleotide (ODN) targeted against PKA RI was administered (0.1 mg/day/rat, i.p.) 1 day before DMBA intubation and during the first 9 days post-DMBA intubation to determine the anticarcinogenic effects.

Results: Antisense RI, in a sequence-specific manner, inhibited the tumor production. At 90 days after DMBA intubation, untreated controls and RI-antisense-treated rats exhibited an average mean number of tumors per rat of 4.2 and 1.8, respectively, and 90% of control and 45% of antisense-treated animals had tumors. The antisense also delayed the first tumor appearance. An increase in RI and PKA-I levels in the mammary gland and liver preceded DMBA-induced tumor production, and antisense down-regulation of RI restored normal levels of PKA-I and PKA-II in these tissues. Antisense RI 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 glands, antisense RI promoted DNA repair processes. In contrast, the CRE transcription-factor decoy could not mimic these effects of antisense RI.

Conclusions: The results demonstrate that RI 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 down-regulating PKA-I.

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