Anti-proliferative effects of 8-chloro-cAMP and other cAMP analogs are unrelated to their effects on protein kinase A regulatory subunit expression
✍ Scribed by Darija Lamb; Robert A. Steinberg
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 148 KB
- Volume
- 192
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Conflicting reports have attributed 8‐chloro‐cAMP (Cl‐cAMP)‐mediated inhibition of tumor cell growth to either a toxic 8‐chloro‐adenosine (Cl‐AdR) breakdown product or a Cl‐cAMP‐mediated decrease in ratio of Type I to Type II regulatory (R) subunits of protein kinase A (PKA). Using the MCF‐7 human breast cancer and S49 mouse lymphoma cell lines as models, we show that the effects of Cl‐cAMP and other cAMP analogs on growth and R subunit expression are unrelated. MCF‐7 cell growth was insensitive to most analogs and inducers of cAMP, but was potently inhibited by Cl‐cAMP acting through uptake and phosphorylation of its Cl‐AdR breakdown product. Possible roles of adenosine receptors or P~2~ purinoceptors in these Cl‐cAMP‐mediated growth effects were ruled out by studies with agonists and antagonists. Cholera toxin markedly decreased the ratio of Type I to Type II R subunits in MCF‐7 cells without affecting growth, while growth inhibitory concentrations of Cl‐cAMP or Cl‐AdR had insignificant effects on this ratio. In S49 cells, where PKA activation is known to inhibit cell growth, PKA‐deficient mutants retained sensitivity to both Cl‐cAMP and the related 8‐bromo‐cAMP. Adenosine kinase (AK)‐deficient S49 cells were inhibited only by higher concentrations of these 8‐halogenated cAMP analogs. Of the commonly used cAMP analogs, only 8‐(4‐chlorophenylthio)‐cAMP acted purely as a cyclic nucleotide—having no effect on PKA‐deficient cells, but strongly inhibiting both wild‐type and AK‐deficient cells. Where growth inhibitory concentrations of most cAMP analogs reduced RI expression in the AK‐deficient mutant, a functionally equivalent concentration of (N^6^, O^2′^)dibutyryl‐cAMP maintained or increased this expression. © 2002 Wiley‐Liss, Inc.