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 Calcium-Sensing Receptor Induces Messenger Ribonucleic Acid of Human Securin, Pituitary Tumor Transforming Gene, in Rat Testicular Cancer

Endocrinology ◽  
2003 ◽  
Vol 144 (12) ◽  
pp. 5188-5193 ◽  
Author(s):  
Jacob Tfelt-Hansen ◽  
Peter Schwarz ◽  
Ernest F. Terwilliger ◽  
Edward M. Brown ◽  
Naibedya Chattopadhyay
Keyword(s):  
Testicular Cancer ◽  
Pituitary Tumor ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Pituitary Tumor Transforming Gene ◽  
Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Calcium Sensing ◽  
High Calcium ◽  
Transforming Gene

Abstract Pituitary tumor transforming gene (PTTG), the human ortholog of securin, is an oncogene. Few normal tissues express PTTG, although in the testis, it is more abundantly expressed. In cancer, however, its wide expression has been directly correlated with the proliferation and angiogenesis, although very little is known about the overall regulation of the PTTG gene. In this study, we investigate the role of the calcium-sensing receptor (CaR), a G protein-coupled receptor (GPCR), in regulating PTTG in a widely used model of humoral hypercalcemia of malignancy, the rat H-500 Leydig cell testicular cancer. We show that extracellular calcium (Ca2+o) up-regulates PTTG mRNA. This up-regulation has a rapid onset, starting at 0.5 h, and remains up-regulated until 40 h. The up-regulation was also Ca2+o concentration dependent, with increases (mean ± se) of 4.22 ± 1.61-fold, 5.11 ± 1.11-fold, and 5.64 ± 1.92-fold at 5, 7.5, and 10 mm calcium, respectively, compared with 0.5 mm Ca2+o. This effect was abolished by overexpression of a dominant-negative CaR (R185Q), thereby confirming that the effect of high Ca2+o is CaR mediated. Another GPCR agonist, ADP, had no effect on PTTG expression. Because PTTG has been reported to induce angiogenesis, we investigated the effect of elevated Ca2+o on vascular endothelial growth factor (VEGF) expression. Indeed high calcium up-regulated VEGF mRNA by 1.59 ± 0.22-fold. In conclusion, we show for the first time that a GPCR, the CaR, stimulates the synthesis of PTTG mRNA in a nonmetastasizing model for humoral hypercalcemia of malignancy and, in the process, might induce angiogenesis via VEGF.

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 The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10

2004 ◽  
Vol 72 (10) ◽  
pp. 5704-5711 ◽  
Author(s):  
Maria K. Dahle ◽  
Gunhild Øverland ◽  
Anders E. Myhre ◽  
Jon Fredrik Stuestøl ◽  
Thomas Hartung ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kupffer Cells ◽  
Interleukin 6 ◽  
Protein Kinase B ◽  
Lipoteichoic Acid ◽  
Phosphatidylinositol 3 Kinase ◽  
Gram Positive ◽  
Tnf Α ◽  
Phosphatidylinositol 3

ABSTRACT Sepsis caused by gram-positive bacteria lacking lipopolysaccharide (LPS) has become a major and increasing cause of mortality in intensive-care units. We have recently demonstrated that the gram-positive-specific bacterial cell wall component lipoteichoic acid (LTA) stimulates the release of the proinflammatory cytokines in Kupffer cells in culture. In the present study, we have started to assess the signal transduction events by which LTA induces the production of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 in rat Kupffer cells. LTA was found to trigger phosphorylation of mitogen-activated protein kinases (MAPK) (p38 MAPK and ERK 1/2) and protein kinase B (PKB). Compared to LPS, LTA was more potent in inducing PKB phosphorylation after 40 min, although we found that the cytokine responses were similar. For both bacterial molecules, blocking phosphatidylinositol 3-kinase (PI3-K; Ly294002) or Janus kinase 2 (JAK-2; AG490) particularly affected the induction of IL-6 and IL-10 release, whereas TNF-α levels were strongly reduced by inhibition of Src family tyrosine kinases (PP2). All three cytokines were reduced by inhibition of p38 MAPK (SB202190) or the broad-range tyrosine kinase inhibitor genistein, whereas IL-6 release was particularly blocked by inhibition of ERK 1/2 (PD98059). Divergences in the regulatory pathways controlling TNF-α, IL-10, and IL-6 production in Kupffer cells following LPS or LTA stimulation may create a basis for understanding how the balance between pro- and anti-inflammatory cytokines is regulated in the liver following infections by gram-positive or gram-negative bacteria.

Protein kinase C and the calcium-sensing receptor in human G cells

2000 ◽  
Vol 94 (1-3) ◽  
pp. 60
Author(s):  
Alison M.J. Buchan ◽  
Paul Squires ◽  
Mark Ring ◽  
Mark Meloche
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Calcium Sensing Receptor ◽  
G Cells ◽  
Calcium Sensing ◽  
Kinase C
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