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Potential of Targeting PDE1C/2A for Suppressing Metastatic Ovarian Cancers

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Technical Report,15 Jun 2013,14 Jun 2014

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Georgia Health Sciences University Research Institute, Inc Augusta United States

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ERK signaling pathway has long been suggested as a therapeutic target for ovarian cancer progression and metastasis. In our previous studies, we showed that 1 high Erk activity is sensitive to the elevation of intracellular cAMP concentration and 2 agents elevating cellular cAMP suppresses growth of aggressive ovarian cancer cells. This proposal is sought to 1 understand molecular mechanisms associated with forskolinPDE2 inhibitor-induced apoptosis of aggressive ovarian cancer cells and 2 to evaluate the translation value of treating aggressive ovarian cancer cells with forskolin and PDE2 inhibitor in anintraperitoneal xenograft model. In first year of the funding, we showed that knockdown of PDE2A rendered ovarian cancer cells susceptible for forskolin-induced cell growth inhibitionapoptosis. We further showed that combined use of forskolin and Bay60-7550 PDE2 inhibitor down regulates the levels of Bcl2, survivin and phosphorylated Akt whereas induces the expression of Bim1. The effect of forskolinBay60-7550 is clearly mediated by PKA because PKA inhibitor H89 abolishedgrowth inhibition caused by forskolinBay60-7550. Results from our first year study elucidate molecular mechanism underlying forskolinPDE2 inhibitor-led ovarian cancer cell growth inhibitionapoptosis and built basis of testing forskolinBay60-7550 in ovarian cancer models.

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