Abstract
The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca2+ 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 Ca2+ 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 ucleotide 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.
| Original language | English |
|---|---|
| Pages (from-to) | 428-438 |
| Number of pages | 11 |
| Journal | Neoplasia |
| Volume | 13 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2011 |
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ASJC Scopus subject areas
- Cancer Research
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The calcium-sensing receptor is necessary for the rapid development of hypercalcemia in human lung squamous cell carcinoma. / Lorch, Gwendolen; Viatchenko-Karpinski, Serge; Ho, Hsiang Ting; Dirksen, Wessel P.; Toribio, Ramiro E.; Foley, John; Györke, Sandor; Rosol, Thomas J.
In: Neoplasia, Vol. 13, No. 5, 05.2011, p. 428-438.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The calcium-sensing receptor is necessary for the rapid development of hypercalcemia in human lung squamous cell carcinoma
AU - Lorch, Gwendolen
AU - Viatchenko-Karpinski, Serge
AU - Ho, Hsiang Ting
AU - Dirksen, Wessel P.
AU - Toribio, Ramiro E.
AU - Foley, John
AU - Györke, Sandor
AU - Rosol, Thomas J.
PY - 2011/5
Y1 - 2011/5
N2 - The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca2+ 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 Ca2+ 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 ucleotide 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.
AB - The calcium-sensing receptor (CaR) is responsible for the regulation of extracellular calcium (Ca2+ 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 Ca2+ 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 ucleotide 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.
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U2 - 10.1593/neo.101620
DO - 10.1593/neo.101620
M3 - Article
VL - 13
SP - 428
EP - 438
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 5
ER -