Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens
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Carlos J. Rodríguez-Hernández1,*, Silvia Mateo-Lozano1,*, Marta García1,*, Carla Casalà1, Ferran Briansó2, Nerea Castrejón1, Eva Rodríguez1, Mariona Suñol3, Angel M. Carcaboso1, Cinzia Lavarino1,4, Jaume Mora1,4, Carmen de Torres1,4
1Developmental Tumor Biology Laboratory, Institut de Recerca Pediàtrica - Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
2Statistics and Bioinformatics Unit, Vall d’Hebron Research Institute, Barcelona, Spain
3Department of Pathology, Institut de Recerca Pediàtrica - Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
4Department of Oncology, Institut de Recerca Pediàtrica - Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
*These authors have contributed equally to this work
Carmen de Torres, e-mail: email@example.com
Keywords: neuroblastoma, calcium-sensing receptor, cinacalcet, ER stress, cancer-testis antigens
Received: October 23, 2015 Accepted: February 05, 2016 Published: February 17, 2016
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. These were predominantly CTAs encoded by genes mapping on chromosome X, which are the most immunogenic. Other modulated genes upon prolonged exposure to cinacalcet were involved in differentiation, cell cycle exit, microenvironment remodeling and calcium signaling pathways. CTAs were up-regulated in PDX and in vitro models as well. Moreover, progressive increase of CaSR expression upon cinacalcet treatment was seen both in vitro and in vivo. In summary, cinacalcet reduces neuroblastoma tumor growth and up-regulates CTAs. This effect represents a therapeutic opportunity and provides surrogate circulating markers of neuroblastoma response to this treatment.
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