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Elevated intracellular cAMP concentration mediates growth suppression in glioma cells.

Abstract
Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.
AuthorsDewi Safitri, Matthew Harris, Harriet Potter, Ho Yan Yeung, Ian Winfield, Liliya Kopanitsa, Fredrik Svensson, Taufiq Rahman, Matthew T Harper, David Bailey, Graham Ladds
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 174 Pg. 113823 (04 2020) ISSN: 1873-2968 [Electronic] England
PMID31987856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020 Elsevier Inc. All rights reserved.
Chemical References
  • Growth Inhibitors
  • Phosphodiesterase Inhibitors
  • Colforsin
  • Cyclic AMP
  • Adenylyl Cyclases
Topics
  • Adenylyl Cyclases (metabolism)
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation (drug effects, physiology)
  • Colforsin (pharmacology)
  • Cyclic AMP (metabolism)
  • Glioma (metabolism, pathology)
  • Growth Inhibitors (pharmacology)
  • Humans
  • Intracellular Fluid (drug effects, metabolism)
  • Phosphodiesterase Inhibitors (pharmacology)
  • Rats

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