Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

Oncotarget
Carlos J Rodríguez-HernándezCarmen de Torres

Abstract

The calcium-sensing receptor is a G protein-coupled receptor that exerts cell-type specific functions in numerous tissues and some cancers. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. We have now assessed cinacalcet, an allosteric activator of the CaSR approved for clinical use, as targeted therapy for this developmental tumor using neuroblastoma cell lines and patient-derived xenografts (PDX) with different MYCN and TP53 status. In vitro, acute exposure to cinacalcet induced endoplasmic reticulum stress coupled to apoptosis via ATF4-CHOP-TRB3 in CaSR-positive, MYCN-amplified cells. Both phenotypes were partially abrogated by phospholipase C inhibitor U73122. Prolonged in vitro treatment also promoted dose- and time-dependent apoptosis in CaSR-positive, MYCN-amplified cells and, irrespective of MYCN status, differentiation in surviving cells. Cinacalcet significantly inhibited tumor growth in MYCN-amplified xenografts and reduced that of MYCN-non amplified PDX. Morphology assessment showed fibrosis in MYCN-amplified xenografts exposed to the drug. Microarrays analyses revealed up-regulation of cancer-testis antigens (CTAs) in cinacalcet-treated MYCN-amplified tumors. The...Continue Reading

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Citations

Jun 1, 2016·Frontiers in Physiology·Silvia Mateo-LozanoCarmen de Torres
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Datasets Mentioned

BETA
GSE73509

Methods Mentioned

BETA
transfection
flow cytometry
xenografts
PCR
Assay
xenograft

Software Mentioned

GraphPad Prism
Ingenuity Pathways Analysis
DAVID
Ingenuity Pathways Analysis ( IPA )
QIAGEN
CellQuest
SPSS
Ingenuity® Pathway

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