Extracellular Calcium-Sensing Receptor (CaR) Expression and Its Potential Role in Parathyroid Hormone-Related Peptide (PTHrP) Secretion in the H-500 Rat Leydig Cell Model of Humoral Hypercalcemia of Malignancy

2000 ◽  
Vol 269 (2) ◽  
pp. 427-432 ◽  
Author(s):  
Jennifer L. Sanders ◽  
Naibedya Chattopadhyay ◽  
Olga Kifor ◽  
Toru Yamaguchi ◽  
Edward M. Brown
Keyword(s):  
Parathyroid Hormone ◽  
Leydig Cell ◽  
Potential Role ◽  
Cell Model ◽  
Extracellular Calcium ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Humoral Hypercalcemia ◽  
Calcium Sensing ◽  
Parathyroid Hormone Related Peptide

Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy

2006 ◽  
Vol 290 (5) ◽  
pp. E761-E770 ◽  
Author(s):  
Naibedya Chattopadhyay
Keyword(s):  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Extracellular Calcium ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Humoral Hypercalcemia ◽  
Cellular Events ◽  
Calcium Sensing ◽  
Parathyroid Hormone Related Peptide

The extracellular calcium-sensing receptor (CaR) plays a key role in the defense against hypercalcemia by “sensing” extracellular calcium (Ca2+o) levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. However, CaR function can be aberrant in certain pathophysiological states, e.g., in some types of cancers known to produce humoral hypercalcemia of malignancy (HHM) in humans and animal models in which high Ca2+o, via the CaR, produces a homeostatically inappropriate stimulation of parathyroid hormone-related peptide (PTHrP) secretion from these tumors. Increased levels of PTHrP set a cycle in motion whereby elevated systemic levels of Ca2+o resulting from its increased bone-resorptive and positive renal calcium-reabsorbing effects give rise to hypercalcemia, which in turn begets worsening hypercalcemia by stimulating further release of PTHrP by the cancer cells. I review the relationship between CaR activation and PTHrP release in normal and tumor cells giving rise to HHM and/or malignant osteolysis and the actions of the receptor on key cellular events such as proliferation, angiogenesis, and apoptosis of cancer cells that will favor tumor growth and osseous metastasis. I also illustrate diverse signaling mechanisms underlying CaR-stimulated PTHrP secretion and other cellular events in tumor cells. Finally, I raise several necessary questions to demonstrate the roles of the receptor in promoting tumors and metastases that will enable consideration of the CaR as a potential antagonizing/neutralizing target for the treatment of HHM.

scholarly journals Calcium-Sensing Receptor Induces Proliferation through p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase But Not Extracellularly Regulated Kinase in a Model of Humoral Hypercalcemia of Malignancy

Endocrinology ◽  
2004 ◽  
Vol 145 (3) ◽  
pp. 1211-1217 ◽  
Author(s):  
J. Tfelt-Hansen ◽  
N. Chattopadhyay ◽  
S. Yano ◽  
D. Kanuparthi ◽  
P. Rooney ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Protein Kinase B ◽  
Mitogenic Effect ◽  
Phosphatidylinositol 3 Kinase ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Calcium Sensing

Abstract Using H-500 rat Leydig cancer cells as a model of humoral hypercalcemia of malignancy (HHM), we previously showed that high Ca2+ induces PTH-related peptide (PTHrP) secretion via the calcium-sensing receptor (CaR) and mitogen- and stress-activated kinases, e.g. MAPK kinase 1 (MEK1), p38 MAPK, and stress-activated protein kinase 1/c-Jun N-terminal kinase. Because cellular proliferation is a hallmark of malignancy, we studied the role of the CaR in regulating the proliferation of H-500 cells. Elevated Ca2+ has a mitogenic effect on these cells that is mediated by the CaR, because the calcimimetic NPS R-467 also induced proliferation. Inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 MAPK but not MEK1 abolished the mitogenic effect. Activation of PI3K by elevated Ca2+ was documented by phosphorylation of its downstream kinase, protein kinase B. Because protein kinase B activation promotes cell survival, we speculated that elevated Ca2+ might protect H-500 cells against apoptosis. Using terminal uridine deoxynucleotidyl nick end labeling staining, we demonstrated that high Ca2+ (7.5 mm) and NPS R-467 indeed protect cells against apoptosis induced by serum withdrawal compared with low Ca2+ (0.5 mm). Because the CaR induces PTHrP secretion, it is possible that the mitogenic and antiapoptotic effects of elevated Ca2+ could be indirect and mediated via PTHrP. However, blocking the type 1 PTH receptor with PTH (7–34) peptide did not alter either high Ca2+-induced proliferation or protection against apoptosis. Taken together, our data show that activation of PI3K and p38 MAPK but not of MEK1/ERK by the CaR promotes proliferation of H-500 cells as well as affords protection against apoptosis. These effects are likely direct without the involvement of PTHrP in an autocrine mode.

scholarly journals Humoral Hypercalcemia of Malignancy with a Parathyroid Hormone-Related Peptide-Secreting Intrahepatic Cholangiocarcinoma Accompanied by a Gastric Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Katsushi Takeda ◽  
Ryosuke Kimura ◽  
Nobuhiro Nishigaki ◽  
Shinya Sato ◽  
Asami Okamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Parathyroid Hormone ◽  
Intrahepatic Cholangiocarcinoma ◽  
Immunohistochemical Staining ◽  
Elevated Serum ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Related Peptide ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Peptide

Humoral hypercalcemia of malignancy (HHM) is caused by the oversecretion of parathyroid hormone-related peptide (PTHrP) from malignant tumors. Although any tumor may cause HHM, that induced by intrahepatic cholangiocarcinoma (ICC) or gastric cancer (GC) is rare. We report here a 74-year-old male who displayed HHM with both ICC and GC and showed an elevated serum PTHrP level. Treatment of the hypercalcemia with saline, furosemide, elcatonin, and zoledronic acid corrected his serum calcium level and improved symptoms. Because treatment of ICC should precede that of GC, we chose chemotherapy with cisplatin (CDDP) and gemcitabine (GEM). Chemotherapy reduced the size of the ICC and decreased the serum PTHrP level. One year after diagnosis, the patient was alive in the face of a poor prognosis for an ICC that produced PTHrP. Immunohistochemical staining for PTHrP was positive for the ICC and negative for the GC, leading us to believe that the cause of the HHM was a PTHrP-secreting ICC. In conclusion, immunohistochemical staining for PTHrP may be useful in discovering the cause of HHM in the case of two cancers accompanied by an elevated serum PHTrP level. Chemotherapy with CDDP and GEM may be the most appropriate treatment for a PTHrP-secreting ICC.

scholarly journals Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription

2007 ◽  
Vol 40 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Cynthia S Ritter ◽  
Sangeeta Pande ◽  
Irina Krits ◽  
Eduardo Slatopolsky ◽  
Alex J Brown
Keyword(s):  
Parathyroid Hormone ◽  
Gene Transcription ◽  
Cell Model ◽  
Decay Rates ◽  
Ionophore A23187 ◽  
Parathyroid Cell ◽  
Mrna Levels ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Extracellular Ca reduces parathyroid hormone (PTH) levels through several mechanisms, but many details of the intracellular steps involved have been difficult to elucidate because of the lack of a suitable parathyroid cell model. The present studies utilized our Ca-responsive bovine parathyroid organoid culture system (pseudoglands) to examine PTH mRNA in intact parathyroid cells. Increasing medium calcium from 0.4 to 3.0 mM reduced PTH mRNA to 20–30% of basal by 16 h. Reducing medium Ca from 3.0 to 0.4 mM restored PTH mRNA levels over a 24-h period. PTH mRNA was also reduced by the calcimimetic R-568, confirming the role of the calcium-sensing receptor. PTH decay rates were determined by placing pseudoglands in either 0.4 or 3.0 mM Ca for 2 h and then blocking gene transcription. PTH mRNA remained stable for at least 24 h in pseudoglands incubated in 0.4 mM Ca, but fell gradually by 62% in the presence of 3.0 mM Ca. Blocking transcription prior to the addition of high-Ca medium dramatically blunted the Ca-induced degradation of PTH mRNA, indicating that acceleration of PTH mRNA decay by Ca requires gene transcription. Pharmacologic investigation of the signaling pathways involved indicated that the Ca-induced reduction of PTH mRNA did not involve MAP kinase, phospholipase D, or cyclic AMP. However, increasing cytosolic Ca with thapsigargin or the Ca ionophore A23187 decreased PTH mRNA levels. In summary, Ca-mediated destabilization of PTH mRNA requires gene transcription and involves increases in cytosolic Ca.

Histopathological Study on the PTHrP-Induced Incisor Lesions in Rats

2003 ◽  
Vol 31 (5) ◽  
pp. 480-485 ◽  
Author(s):  
Atsuhiko Kato ◽  
Masami Suzuki ◽  
Yayoi Karasawa ◽  
Tetsuro Sugimoto ◽  
Kunio Doi
Keyword(s):  
Parathyroid Hormone ◽  
Rat Model ◽  
Causative Factor ◽  
Histopathological Study ◽  
Middle Region ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Cell Height ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Peptide ◽  
Calcification Process

Parathyroid hormone related peptide (PTHrP) was discovered as a causative factor of humoral hypercalcemia of malignancy (HHM). The present study elucidates the histopathological characters of incisor lesions in the HHM rat model. Nude rats were implanted with PTHrP-expressing tumor (LC-6) cells, maintained for 12 weeks, after which the mandibular incisors were collected. Incisor fractures were observed grossly. Microscopically, hypercalcified dentin, dentin niche with osteodentin, and thinning of dentin were observed. Hypercalcified dentin was observed as a basophilic line of calcified dentin without associated odontoblastic changes, whereas dentin niche and thinning of dentin occurred with osteodentin and loss of cell height, respectively. In contrast with hypercalcified dentin, which was distributed throughout the dentin, dentin niche and thinning of dentin were localized to the labial area of the apical and middle region, and to the labial and lingual areas of the middle and incisal region, respectively. These results suggest that hypercalcemia affected the entire calcification process resulting in hypercalcified dentin, and that high PTHrP concentrations affected selective populations of odontoblasts resulting in formation of dentin niche and thinning of dentin. The localization of dentin niche and thinning of dentin also suggest that PTHrP may also be involved odontoblastic development in the rat.

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