CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway.
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 alpha-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.
Graziani
Grazia
G
Department of Neuroscience, University of Rome Tor Vergata, Italy.
Tentori
Lucio
L
Portarena
Ilaria
I
Barbarino
Marcella
M
Tringali
Giuseppe
G
Pozzoli
Giacomo
G
Navarra
Pierluigi
P
D000230:Adenocarcinoma / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D023282:Nuclease Protection Assays; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019098:Telomerase