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Growth Hormone Inhibits Apoptosis in Human Colonic Cancer Cell Lines: Antagonistic Effects of Peroxisome Proliferator Activated Receptor- Ligands

Department of Endocrinology and Metabolism (F.B., F.U., F.R., D.R., S.B., C.C., M.G., E.M.) and Transfusional Unit (R.V., C.G.), University of Pisa, 56124 Pisa, Italy; and Division of Endocrinology (L.B.), University of Insubria, 21100 Varese, Italy

Address all correspondence and requests for reprints to: Fausto Bogazzi, Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Ospedale di Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: f.bogazzi{at}endoc.med.unipi.it or fbogazzi{at}hotmail.com.

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor- (PPAR) activation enhances apoptosis, and a link between GH and PPAR in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPAR ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05–50 nM GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55–85% reduction of PPAR expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1–50 µM ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPAR expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPAR. The reduced GH-dependent apoptosis can be overcome by PPAR ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.

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