Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

Rodríguez-Hernández, Carlos J.; García, Marta; Casalà, Carla; Briansó, Ferran; Castrejón, Nerea; Rodríguez, Elisa Boucourt; Suñol, Mariona; Carcaboso, Ángel M.; Lavarino, Cinzia; Mora, Jaume; Torres, Carmen de

doi:10.18632/oncotarget.7448

Cited by 20 publications

(31 citation statements)

References 48 publications

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“…Genetic variant rs1501899 was also significantly associated with down-regulation of CaSR mRNA in the absence of CASR epigenetic silencing (Table 4). 41.67 (20) 58.33 (28) 66.67 (32) 33.33 (16) 79.17 (38) 20.83 (10) 70.83 (34) 29.17 (14) rs7652589 G/G 55 (11) 32.14 (9) 37.5 (12) 50 (8) 44.74 (17) 30 (3) 44.12 (15) 35.71 (5)…”

Section: Genetic Variants Rs7652589 and Rs1501899 Are Independently Amentioning

confidence: 99%

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Genetic variants in the promoter region of the calcium‐sensing receptor gene are associated with its down‐regulation in neuroblastic tumors

Masvidal

Iniesta

García

et al. 2016

Molecular Carcinogenesis

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We have previously reported that the calcium-sensing receptor (CaSR) is expressed in benign, differentiated neuroblastic tumors, and epigenetically silenced in undifferentiated, malignant cases. Furthermore, cinacalcet, an allosteric activator of the CaSR, reduces neuroblastoma tumor growth in preclinical models. However, to identify patients that might benefit from this treatment, a complete understanding of mechanisms governing CaSR expression in these tumors would be required. We have now analyzed two polymorphisms in the promoter region of the CASR gene (rs7652589 and rs1501899) by allelic discrimination in neuroblastoma patients and cell lines. Association of genotypes and haplotypes with CaSR mRNA levels and CASR promoter P2 methylation status was determined. Data presented show that minor alleles rs7652589 and rs1501899, present either in homo- or heterozygosis, were correlated with reduced CaSR mRNA levels in matching primary tumors and this association was independent of CASR promoter P2 hypermethylation. Haplotype AA was independently associated with reduced CaSR expression after adjusting by promoter P2 methylation status. These polymorphisms were identified in some ganglioneuromas in which CaSR expression is low despite exhibiting a high degree of differentiation. Furthermore, homozygous variants rs7652589 and rs1501899 were detected in SH-SY5Y cells, which are devoid of CaSR expression in the absence of hypermethylation of CASR promoter P2. In summary, minor alleles rs7652589 and rs1501899 are associated with reduced CaSR expression in neuroblastic tumors and neuroblastoma cell lines in which the CASR gene promoter P2 is not hypermethylated. Therefore, they potentially represent an additional mechanism of CASR transcriptional regulation in this group of developmental malignancies. © 2016 Wiley Periodicals, Inc.

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Section: Genetic Variants Rs7652589 and Rs1501899 Are Independently Amentioning

confidence: 99%

“…67.86 (19) 62.5 (20) 50 (8) 55.26 (21) 70 (7) 55.88 (19) 64.29 ( 57.14 (16) 62.5 (20) 68.75 (11) 68.42 (26) 50 (5) 67.65 (23) 57.14 (8) A-A Genotype and haplotype frequencies and absolute counts in brackets. P from Chi-square or Fisher exact tests.…”

Section: Genetic Variants Rs7652589 and Rs1501899 Are Independently Amentioning

confidence: 99%

Genetic variants in the promoter region of the calcium‐sensing receptor gene are associated with its down‐regulation in neuroblastic tumors

Masvidal

Iniesta

García

et al. 2016

Molecular Carcinogenesis

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“…Finally, a recent study has shown that cinacalcet, an allosteric activator of the CaSR approved for clinical use (Nemeth et al, 1998 ), inhibits neuroblastoma tumor growth in vitro and in vivo (Rodríguez-Hernández et al, 2016 ). Mechanisms involved include ER stress coupled to apoptosis dependent on phospholipase C activation in MYCN -amplified neuroblastoma cells and, irrespective of MYCN status, differentiation of surviving cells.…”

Section: Role Of Casr In Differentiation Of Tumoral Developing Nervoumentioning

confidence: 99%

Regulation of Differentiation by Calcium-Sensing Receptor in Normal and Tumoral Developing Nervous System

García¹,

Rodríguez-Hernández²,

Torres³

2016

Front. Physiol.

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During normal development of the nervous system (NS), neural progenitor cells (NPCs) produce specialized populations of neurons and glial cells upon cell fate restriction and terminal differentiation. These sequential processes require the dynamic regulation of thousands of genes. The calcium-sensing receptor (CaSR) is temporally and spatially regulated in both neurons and glial cells during development of the NS. In particular, CaSR expression and function have been shown to play a significant role during differentiation of NPCs toward the oligodendrocyte lineage and also in maturation of cerebellar granule cell precursors (GCPs). Moreover, CaSR regulates axonal and dendritic growth in both central and peripheral nervous systems (PNSs), a process necessary for proper construction of mature neuronal networks. On the other hand, several lines of evidence support a role for CaSR in promotion of cell differentiation and inhibition of proliferation in neuroblastoma, a tumor arising from precursor cells of developing PNS. Thus, among the variety of NS functions in which the CaSR participates, this mini-review focuses on its role in differentiation of normal and tumoral cells. Current knowledge of the mechanisms responsible for CaSR regulation and function in these contexts is also discussed, together with the therapeutic opportunities provided by CaSR allosteric modulators.

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“…Indeed, ectopic re-expression of the CaSR in MYCN-amplified neuroblastoma cells, which are normally CaSR negative, reduced xenograft growth[ 71 ]. In addition, treatment with cinacalcet, a positive allosteric modulator of the CaSR, was able to induce the expression of differentiation markers, to inhibit cell proliferation in vitro and the growth of mouse tumour xenografts in vivo [ 22 ].…”

Section: Role Of the Casr In Cancermentioning

confidence: 99%

Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives

Iamartino¹,

Elajnaf²,

Kállay³

et al. 2018

WJG

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The extracellular calcium-sensing receptor (CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the CaSR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitis-associated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.

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Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

Cited by 20 publications

References 48 publications

Genetic variants in the promoter region of the calcium‐sensing receptor gene are associated with its down‐regulation in neuroblastic tumors

Genetic variants in the promoter region of the calcium‐sensing receptor gene are associated with its down‐regulation in neuroblastic tumors

Regulation of Differentiation by Calcium-Sensing Receptor in Normal and Tumoral Developing Nervous System

Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives

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