TY - JOUR

T1 - Calcium-Sensing Receptor Induces Messenger Ribonucleic Acid of Human Securin, Pituitary Tumor Transforming Gene, in Rat Testicular Cancer

AU - Tfelt-Hansen, Jacob

AU - Schwaez, Peter

AU - Terwilliger, Ernest F.

AU - Brown, Edward M.

AU - Chattopadhyay, Naibedya

PY - 2003/12/1

Y1 - 2003/12/1

N2 - 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) upregulates 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 Ca 2+ 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.

AB - 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) upregulates 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 Ca 2+ 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.

UR - http://www.scopus.com/inward/record.url?scp=0344825840&partnerID=8YFLogxK

U2 - 10.1210/en.2003-0520

DO - 10.1210/en.2003-0520

M3 - Journal article

C2 - 12970167

AN - SCOPUS:0344825840

VL - 144

SP - 5188

EP - 5193

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0013-7227

IS - 12

ER -