The calcium-sensing receptor is silenced by genetic and epigenetic mechanisms in unfavorable neuroblastomas and its reactivation induces ERK1/2-dependent apoptosis

Casalà, Carla; Gil-Guiñón, Estel; Ordóñez, José Luis; Miguel-Queralt, Solange; Rodríguez, Elisa Boucourt; Galván, Patricia; Lavarino, Cinzia; Munell, Francina; Álava, Enrique de; Mora, Jaume; Torres, Carmen de

doi:10.1016/j.bone.2012.08.079

Cited by 5 publications

(12 citation statements)

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“…Total RNA was isolated using TriReagent (Sigma‐Aldrich, St Louis, MO, USA). Retrotranscription, PCR and qPCR were carried out as described (Casalà et al ., ; de Torres et al ., ). Real‐time PCR runs were performed in a QuantStudio 6 (Applied Biosystems, Forster City, CA, USA) using gene‐specific Assays on Demand and Taqman Universal PCR Master Mix or specific primers and SYBRGreen (Applied Biosystems) (Table S2).…”

Section: Methodsmentioning

confidence: 98%

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Parathyroid hormone‐like hormone plays a dual role in neuroblastoma depending on PTH1R expression

et al. 2019

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We have previously reported the expression of parathyroid hormone‐like hormone ( PTHLH ) in well‐differentiated, Schwannian stroma‐rich neuroblastic tumors. The aim of this study was to functionally assess the role of PTHLH and its receptor, PTH 1R, in neuroblastoma. Stable knockdown of PTHLH and PTH 1R was conducted in neuroblastoma cell lines to investigate the succeeding phenotype induced both in vitro and in vivo . Downregulation of PTHLH reduced MYCN expression and subsequently induced cell cycle arrest, senescence, and migration and invasion impairment in a MYCN ‐amplified, TP 53 ‐mutated neuroblastoma cell line. These phenotypes were associated with reduced tumorigenicity in a murine model. We also show that PTHLH expression is not under the control of the calcium‐sensing receptor in neuroblastoma. Conversely, its production is stimulated by epidermal growth factor receptor ( EGFR ). Accordingly, irreversible EGFR inhibition with canertinib abolished PTHLH expression. The oncogenic role of PTHLH appeared to be a consequence of its intracrine function, as downregulation of its receptor, PTH 1R, increased anchorage‐independent growth and induced a more undifferentiated, invasive phenotype. Respectively, high PTH 1R mRNA expression was found in MYCN nonamplified primary tumors and also significantly associated with other prognostic factors of good outcome. This study provides the first evidence of the dual role of PTHLH in the behavior of neuroblastomas. Moreover, the identification of EGFR as a transcriptional regulator of PTHLH in neuroblastoma provides a novel therapeutic opportunity to promote a less aggressive tumor phenotype through irreversible inhibition of EGFR tyrosine kinase activity.

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Section: Methodsmentioning

confidence: 98%

“…Over the past few years, we have reported that the calcium‐sensing receptor (CaSR) acts as a tumor suppressor in neuroblastoma (Casalà et al ., ; Rodríguez‐Hernández et al ., ). CaSR is a G protein‐coupled receptor critically required to regulate parathyroid hormone (PTH) secretion and calcium homeostasis (Brennan et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone‐like hormone plays a dual role in neuroblastoma depending on PTH1R expression

et al. 2019

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“…Approximately 98% of neuroblastomas are associated with spontaneous mutations in a variety of genes (Aygun, 2018). Analysis of mRNA from neuroblastoma tumors indicates that although the CaSR is expressed in benign differentiated tumors, epigenetic hypermethylation of the CASR P2 promoter region silences CASR transcription in some aggressive neuroblastomas (de Torres et al, 2009;Casalà et al, 2013). Similarly, two noncoding CASR SNPs (rs7652579 and rs1501899) that reduce CaSR expression are present in homozygous or heterozygous form in 58% of neuroblastoma tumors but in only 47% of the general population (Masvidal et al, 2017).…”

Section: K Calcium-sensing Receptor In the Brain And Nervous Systemmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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“…In addition to genomic instability, epigenetic instability leads to irregular methylation of tumor suppressor genes. Hypermethylation of particular regions within the CpG islands encompassing the CASR gene promoter 2 was shown in 25% of neuroblastoma primary tumors and was associated with decreased CASR messenger RNA expression and several predictors of poor outcome in neuroblastomas, including MYC amplification . One study reported that hypermethylation of CASR was detected in 69% of colorectal cancer tissues and 90% of lymph node metastatic tissues, as well as significantly correlated with decreased CASR expression .…”

Section: Discussionmentioning

confidence: 99%

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

Momen-Heravi

Masugi

Qian

et al. 2017

Intl Journal of Cancer

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Although experimental evidence suggests calcium-sensing receptor (CASR) as a tumor-suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses’ Health Study and the Health Professionals Follow-up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer-specific and all-cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, expressions of PTGS2, VDR, and CTNNB1, and mutations of KRAS, BRAF, and PIK3CA. There were 240 colorectal cancer-specific deaths and 427 all-cause deaths. The median follow-up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared to patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer-specific mortality were 0.80 [95% confidence interval (CI): 0.55-1.16] in patients with moderate CASR expression, and 0.50 (95% CI: 0.32-0.79) in patients with intense CASR expression (p-trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64-1.13) and 0.81 (0.58-1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer-specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression.

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The calcium-sensing receptor is silenced by genetic and epigenetic mechanisms in unfavorable neuroblastomas and its reactivation induces ERK1/2-dependent apoptosis

Cited by 5 publications

References 0 publications

Parathyroid hormone‐like hormone plays a dual role in neuroblastoma depending on PTH1R expression

Parathyroid hormone‐like hormone plays a dual role in neuroblastoma depending on PTH1R expression

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

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