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CRH Inhibits Cell Growth of Human Endometrial Adenocarcinoma Cells via CRH-Receptor 1-Mediated Activation of cAMP-PKA Pathway

Institute of Pharmacology, Catholic University Medical School (G.T., G.P., M.B., P.N.), Rome 00168, Italy; Pharmacology and Medical Oncology Section, Department of Neuroscience, University of Rome "Tor Vergata" (G.G., L.T., I.P.), Rome 00133, Italy

Address all correspondence and requests for reprints to: Prof. Pierluigi Navarra, Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1-00168 Rome, Italy. E-mail: . pnavarra{at}rm.unicatt.it

CRH produced by human endometrial cells exerts decidualizing activity via an autocrine mechanism mediated via CRH-R1 receptors. We postulated that such activity exerted by CRH on normal endometrial cells might translate into an antiproliferative action on endometrial-derived malignancies, provided that neoplastic cells maintain the expression of CRH receptors. In this light, here we investigated the possible antiproliferative effects of CRH in an adenocarcinoma cell line derived from human endometrium.

CRH induces time- and concentration-dependent inhibition of Ishikawa cell growth, the maximal effect (50% inhibition) being achieved after 3 d of treatment with 10^-7 M CRH. A decrease in telomerase activity, which paralleled tumor growth inhibition, was also observed in CRH-treated samples. The antiproliferative effect was confirmed by colony-formation assay for long-term survival. This effect was counteracted in a concentration-dependent manner by both -helical CRH and astressin; the former also showed intrinsic inhibitory activity. These findings suggested the involvement of CRH-R1 receptor subtype; this hypothesis was confirmed by RNase protection analysis showing the expression of human CRH-R1 mRNA. Experiments with the PKA inhibitor 14–22 amide and forskolin, as well as the measurement of intracellular cAMP, suggested the downstream involvement of cAMP-PKA pathway in CRH-induced inhibition of Ishikawa cell growth.

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