Cyclic AMP Phosphodiesterase-4 in Brain Tumor Biology: Immunochemical Analysis

  • B. Mark Woerner
  • Joshua B. Rubin
Part of the Methods of Cancer Diagnosis, Therapy and Prognosis book series (HAYAT, volume 8)


Central to advancing the care for patients with malignant neoplasms are efforts to delineate how cancer cells differ from their normal counterparts, and the identification of biological targets whose activity, when normalized, corrects the cancer phenotype and re-establishes normal growth control. In this regard we and others have described the tumor promoting actions of cyclic adenosine monophos­phate (cAMP) phosphodiesterases and the antitumor effects of phosphodiesterase inhibitors. In the following chapter we will focus on the unique biology of the cAMP phosphodiesterase-4 (PDE4) family of cAMP hydrolases as it pertains to brain tumors and the experimental challenges that arise when studying patterns of PDE4 expression.


PDE4 Activity DAOY Cell Normal Swine Serum PDE4 Isoforms PDE4 Family 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Acknowledgements. The authors thank Nicole Warrington for critical reading of the manuscript. This work was supported by the NCI/NIH (CA118389) to JBR.


  1. Chen, T.C., Wadsten, P., Su, S., Rawlinson, N., Hofman, F.M., Hill, C.K., and Schonthal, A.H. (2002) The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol. Ther. 1:268–276PubMedGoogle Scholar
  2. Cherry, J.A., and Davis, R.L. (1999) Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J. Comp. Neurol. 407:287–301PubMedCrossRefGoogle Scholar
  3. Conti, M., and Jin, S.L. (1999) The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucl. Acid Res. Mol. Biol. 63:1–38CrossRefGoogle Scholar
  4. Drees, M., Zimmermann, R., and Eisenbrand, G. (1993) 3’,5’-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. Cancer Res. 53:3058–3061PubMedGoogle Scholar
  5. Dyke, H.J., and Montana, J.G. (2002) Update on the therapeutic potential of PDE4 inhibitors. Expert Opin. Investig. Drugs 11: 1–13PubMedCrossRefGoogle Scholar
  6. Furman, M.A., and Shulman, K. (1977) Cyclic AMP and adenyl cyclase in brain tumors. J. Neurosurg. 46:477–483PubMedCrossRefGoogle Scholar
  7. Goldhoff, P., Warrington, N.M., Limbrick, D.D. Jr., Hope, A., Woerner, B.M., Jackson, E., Perry, A., Piwnica-Worms, D., and Rubin, J.B. (2008) Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin. Cancer Res. 14: 7717–7725PubMedCrossRefGoogle Scholar
  8. Huston, E., Gall, I., Houslay, T.M., and Houslay, M.D. (2006) Helix-1 of the cAMP-specific phosphodiesterase PDE4A1 regulates its phospholipase-D-dependent redistribution in response to release of Ca2+. J. Cell Sci. 119:3799–3810PubMedCrossRefGoogle Scholar
  9. Lugnier, C. (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol. Ther. 109:366–398PubMedCrossRefGoogle Scholar
  10. Lynch, M.J., Baillie, G.S., Mohamed, A., Li, X., Maisonneuve, C., Klussmann, E., van Heeke, G., and Houslay, M.D. (2005) RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J. Biol. Chem. 280:33178–3389PubMedCrossRefGoogle Scholar
  11. Lynch, M.J., Hill, E.V., and Houslay, M.D. (2006) Intracellular targeting of phosphodiesterase-4 underpins compartmentalized cAMP signaling. Curr. Top. Dev. Biol. 75:225–259PubMedCrossRefGoogle Scholar
  12. Marko, D., Pahlke, G., Merz, K.H., and Eisenbrand, G. (2000) Cyclic 3′,5′-nucleotide phosphodiesterases: potential targets for anticancer therapy. Chem. Res. Toxicol. 13:944–948Google Scholar
  13. Marko, D., Romanakis, K., Zankl, H., Furstenberger, G., Steinbauer, B., and Eisenbrand, G. (1998) Induction of apoptosis by an inhibitor of cAMP-specific PDE in malignant murine carcinoma cells overexpressing PDE activity in comparison to their nonmalignant counterparts. Cell Biochem. Biophys. 28:75–101PubMedCrossRefGoogle Scholar
  14. McCahill, A., McSorley, T., Huston, E., Hill, E.V., Lynch, M.J., Gall, I., Keryer, G., Lygren, B., Tasken, K., van Heeke, G., and Houslay, M.D. (2005) In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region. Cell Signal 17:1158–1173PubMedCrossRefGoogle Scholar
  15. McEwan, D.G., Brunton, V.G., Baillie, G.S., Leslie, N.R., Houslay, M.D., and Frame, M.C. (2007) Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res. 67:5248–5257PubMedCrossRefGoogle Scholar
  16. Merz, K.H., Marko, D., Regiert, T., Reiss, G., Frank, W., and Eisenbrand, G. (1998) Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J. Med. Chem. 41:4733–4743PubMedCrossRefGoogle Scholar
  17. Ogawa, R., Streiff, M.B., Bugayenko, A., and Kato, G.J. (2002) Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Blood 99: 3390–3397PubMedCrossRefGoogle Scholar
  18. Ponsioen, B., Zhao, J., Riedl, J., Zwartkruis, F., van der Krogt, G., Zaccolo, M., Moolenaar, W.H., Bos, J.L., and Jalink, K. (2004) Detecting cAMP-induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator. EMBO Rep. 5:1176–1180PubMedCrossRefGoogle Scholar
  19. Racagni, G., Pezzotta, S., Giordana, M.T., Iuliano, E., Mocchetti, I., Spanu, G., Sangiovanni, G., and Paoletti, P. (1983) Cyclic nucleotides in experimental and human brain tumors. J. Neurooncol. 1:61–67PubMedCrossRefGoogle Scholar
  20. Scotland, G., and Houslay, M.D. (1995) Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyltransferase. Biochem. J. 308 (Pt 2):673–681PubMedGoogle Scholar
  21. Shakur, Y., Pryde, J.G., and Houslay, M.D. (1993) Engineered deletion of the unique N-terminal domain of the cyclic AMP-specific phosphodiesterase RD1 prevents plasma membrane association and the attainment of enhanced thermostability without altering its sensitivity to inhibition by rolipram. Biochem. J. 292 (Pt 3):677–686PubMedGoogle Scholar
  22. Siegmund, B., Welsch, J., Loher, F., Meinhardt, G., Emmerich, B., Endres, S., and Eigler, A. (2001) Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis. Leukemia 15:1564–1571PubMedCrossRefGoogle Scholar
  23. Spina, D. (2008) PDE4 inhibitors: current status. Br. J. Pharmacol. 155:308–315PubMedCrossRefGoogle Scholar
  24. Sunahara, R.K., and Taussig, R. (2002) Isoforms of mammalian adenylyl cyclase: multiplicities of signaling. Mol. Interv. 2:168–184PubMedCrossRefGoogle Scholar
  25. Wachtel, H., and Schneider, H.H. (1986) Rolipram, a novel antidepressant drug, reverses the hypothermia and hypokinesia of monoamine-depleted mice by an action beyond postsynaptic monoamine receptors. Neuropharmacology 25:1119–1126PubMedCrossRefGoogle Scholar
  26. Warrington, N.M., Woerner, B.M., Daginakatte, G.C., Dasgupta, B., Perry, A., Gutmann, D.H., and Rubin, J.B. (2007) Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res. 67:8588–8595PubMedCrossRefGoogle Scholar
  27. Yang, L., Jackson, E., Woerner, B.M., Perry, A., Piwnica-Worms, D., and Rubin, J.B. (2007) Blocking CXCR4-mediated cyclic amp suppression inhibits brain tumor growth in vivo. Cancer Res. 67:651–658PubMedCrossRefGoogle Scholar

Copyright information

© Springer Netherlands 2011

Authors and Affiliations

  • B. Mark Woerner
    • 1
  • Joshua B. Rubin
    • 1
  1. 1.Division of Pediatric Hematology/Oncology, Department of PediatricsWashington University, School of MedicineSt. LouisUSA

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