Calcium-sensing receptor in cancer: good cop or bad cop?
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INVITED REVIEW
Calcium-sensing receptor in cancer: good cop or bad cop? Bandana Chakravarti Æ Shailendra Kumar Dhar Dwivedi Æ Ambrish Mithal Æ Naibedya Chattopadhyay
Received: 28 July 2008 / Accepted: 21 October 2008 / Published online: 15 November 2008 Ó Humana Press Inc. 2008
Abstract The extracellular calcium-sensing receptor (CaR) is a versatile ‘sensor’ for di- and polycationic molecules in the body. CaR plays a key role in the defense against hypercalcemia by ‘‘sensing’’ extracellular calcium levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. Although mutation of CaR gene has so far not been associated with any malignancy, aberrant functions of CaR have implications in malignant progression. One situation is loss of CaR expression, resulting in loss of growth suppressing effects of elevated extracellular Ca2? by CaR, reported in parathyroid adenoma and in colon carcinoma. Another situation is activation of CaR, resulting in increased production of parathyroid hormone-related peptide (PTHrP), a primary causal factor in hypercalcemia of malignancy and a contributor to metastatic processes involving bone. CaR signaling and effects have been studied in several cancers including ovarian cancers, gastrinomas, and gliomas in addition to comparatively detailed studies in breast, prostate, and colon cancers. Studies on H-500 rat Leydig cells, a xenotransplantable model of humoral hypercalcemia of malignancy has shed much light on the mechanisms of CaR-induced cancer cell growth and survival. Pharmacological agonists and antagonists of CaR hold therapeutic promise depending on whether activation of CaR is
Bandana Chakravarti and Shailendra Kumar Dhar Dwivedi contributed equally. B. Chakravarti (&) S. K. D. Dwivedi N. Chattopadhyay Division of Endocrinology, Central Drug Research Institute, Chattar Manzil, P.O. Box 173, Lucknow, India e-mail: [email protected] A. Mithal Indraprastha Apollo Hospital, New Delhi, India
required such as in case of colon cancer or inactivating the receptor is required as in the case of breast- and prostate tumors. Keywords Hypercalcemia of malignancy Epidermal growth factor receptor Parathyroid hormone-related protein Wnt signaling Metastases
Introduction Calcium is required for all living cells to maintain their normal structure and function [1, 2]. Calcium signaling occupies a pre-eminent position in the signal transduction system of the cell by virtue of its participation in a variety of physiological functions, biological events associated with cell proliferation and apoptosis [3, 4] as well as cell differentiation [5]. Calcium signaling is also an important feature of cell adhesion and motility [6, 7]. Certainly all these events are integral to normal cell functions, and disruptions in calcium signaling are well-established features in the genesis and progression of cancer [8]. Role of calcium as a second messenger has traditionally received more attention, as a multitude of growth factors and cytokines signal through this ub
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