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Calcium-Sensing Receptor Induces Messenger Ribonucleic Acid of Human Securin, Pituitary Tumor Transforming Gene, in Rat Testicular Cancer

Division of Endocrinology, Diabetes, and Hypertension (J.T.-H., E.M.B., N.C.), Department of Medicine and Membrane Biology Program, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, 02115; Osteoporosis and Bone Metabolic Unit (P.S.), Department of Clinical Biochemistry and Endocrinology, Copenhagen University Hospital Hvidovre, Copenhagen DK-2650, Denmark; and Division of Experimental Medicine (E.F.T.), Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Jacob Tfelt-Hansen, Endocrine-Hypertension Division, Department of Medicine and Membrane Biology Program, Brigham and Women’s Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: jtfelt{at}rics.bwh.harvard.edu.

Abstract

Pituitary tumor transforming gene (PTTG), the human ortholog of securin, is an oncogene. Few normal tissues express PTTG, although in the testis, it is more abundantly expressed. In cancer, however, its wide expression has been directly correlated with the proliferation and angiogenesis, although very little is known about the overall regulation of the PTTG gene. In this study, we investigate the role of the calcium-sensing receptor (CaR), a G protein-coupled receptor (GPCR), in regulating PTTG in a widely used model of humoral hypercalcemia of malignancy, the rat H-500 Leydig cell testicular cancer. We show that extracellular calcium (Ca²⁺_o) up-regulates PTTG mRNA. This up-regulation has a rapid onset, starting at 0.5 h, and remains up-regulated until 40 h. The up-regulation was also Ca²⁺_o concentration dependent, with increases (mean ± SE) of 4.22 ± 1.61-fold, 5.11 ± 1.11-fold, and 5.64 ± 1.92-fold at 5, 7.5, and 10 mM calcium, respectively, compared with 0.5 mM Ca²⁺_o. This effect was abolished by overexpression of a dominant-negative CaR (R185Q), thereby confirming that the effect of high Ca²⁺_o is CaR mediated. Another GPCR agonist, ADP, had no effect on PTTG expression. Because PTTG has been reported to induce angiogenesis, we investigated the effect of elevated Ca²⁺_o on vascular endothelial growth factor (VEGF) expression. Indeed high calcium up-regulated VEGF mRNA by 1.59 ± 0.22-fold. In conclusion, we show for the first time that a GPCR, the CaR, stimulates the synthesis of PTTG mRNA in a nonmetastasizing model for humoral hypercalcemia of malignancy and, in the process, might induce angiogenesis via VEGF.

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