title: The calcium-sensing receptor is necessary for the rapid development of hypercalcemia in human lung squamous cell carcinoma.
abstract: The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca(2+) (o)) homeostasis. CaR activation has been shown to increase proliferation in several cancer cell lines; however, its presence or function has never been documented in lung cancer. We report that Ca(2+) (o)-activated CaR results in MAPK-mediated stimulation of parathyroid hormone-related protein (PTHrP) production in human lung squamous cell carcinoma (SCC) lines and humoral hypercalcemia of malignancy (HHM) in vivo. Furthermore, a single nucleotide polymorphism in CaR identified from a hypercalcemia-inducing lung SCC reduced the receptor's activation threshold leading to increased PTHrP expression and secretion. Increasing the expression of either wild-type CaR or a CaR variant with a single nucleotide polymorphism in the cytoplasmic domain was both necessary and sufficient for lung SCC to induce HHM. Because lung cancer patients who frequently develop HHM and PTHrP expression in lung cancer has been only partially explained, the significance of our findings indicates that CaR variants may provide a positive feedback between PTHrP and calcium and result in the syndrome of HHM.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA. gwendolen.lorch@cvm.osu.edu
authors.forename: Gwendolen
authors.initials: G
authors.lastname: Lorch
authors.forename: Serge
authors.initials: S
authors.lastname: Viatchenko-Karpinski
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.forename: Wessel P
authors.initials: WP
authors.lastname: Dirksen
authors.forename: Ramiro E
authors.initials: RE
authors.lastname: Toribio
authors.forename: John
authors.initials: J
authors.lastname: Foley
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism* / Q000503:physiopathology*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium