The role of calcium-sensing receptor and signalling pathways in the pathophysiology in two in vitro models of malignant hypercalcemia: the rat rice H-500 Leydig testis cancer and prostate cancer (PC-3) cells. Expression and regulation of pituitary tumor transforming gene in Leydig testis cancer and astrocyte and astrocytoma cells.

INTRODUCTION Calcium is a crucial biological cation. The body has a fine tuned system to regulate the level of calcium in the extracellular fluid. The system regulating extracellular calcium is termed the calcium homeostatic system. The calcium homeostatic system involves several hormones and organs. The hormones involved comprise, amongst others, the parathyroid hormone, vitamin D and calcitonin. The organs involved are mainly the parathyroid glands, kidneys, skeleton and intestine. Calcium is very important extracellularly as well as intracellularly. In the cell Ca2+ serves as an intracellular messenger that participates in muscle contraction, neurotransmission, and enzyme activity (53). Outside the cell calcium probably plays just as important roles for the organism as it does inside the cell. The extracellular calcium ion is important as the cation participates in blood clotting, contributes to maintaining the membrane potential across the cell membrane, functions as a reservoir of calcium e.g. during every heart beat, and controls the release of hormones crucial for calcium homeostasis. Thus calcium controls a plethora of essential cellular functions, ranging from release of hormone and muscle contraction to gene expression. These functions in turn control cell growth, proliferation and cell death. One of the key players in extracellular calcium homeostasis is the calcium-sensing receptor (CaR). The two major functions of this receptor in calcium homeostasis are to inhibit PTH release from the parathyroid gland and to inhibit renal reabsorption of calcium. Besides being expressed in the chief cells of the parathyroid gland and along the nephron of the kidney, the CaR has also been found to be functionally expressed in tissues not related to calcium homeostasis, including some cancer cells. The loss of regulation of growth is a key factor in the development of cancer. The CaR has been implicated by circumstantial evidence as well as proven to be involved in the progression of cancer disease in vitro (218). But much remain to be learned about the function of the CaR expressed in many cancer cells. Likewise the identification of many intracellular signalling pathways has provided a novel opportunity to understand the molecular mechanism behind the receptor’s function in cancer cells. One such novel molecule is the pituitary tumor transforming gene initial found in pituitary adenomas and subsequently expressed in the fetal liver as well as in the testis. Furthermore studies have shown a correlation between the expression of pituitary tumor transforming gene and degree of malignancy in the e.g. colon, and increasing evidence points toward a role of the protein in the genesis of cancer. The pituitary tumor transforming gene is a key player in the anaphase of cell division, and no previous studies have investigated the regulation of this protein by the CaR.