AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia
Neuroblastoma is the most common extracranial solid tumor of childhood, with heterogeneous clinical manifestations ranging from spontaneous regression to aggressive metastatic disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that senses plasmatic fluctuation in the...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4323 |
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| author | Eliana Gonçalves-Alves Marta Garcia Carlos J. Rodríguez-Hernández Soledad Gómez-González Rupert C. Ecker Mariona Suñol Oscar Muñoz-Aznar Angel M. Carcaboso Jaume Mora Cinzia Lavarino Silvia Mateo-Lozano |
| author_facet | Eliana Gonçalves-Alves Marta Garcia Carlos J. Rodríguez-Hernández Soledad Gómez-González Rupert C. Ecker Mariona Suñol Oscar Muñoz-Aznar Angel M. Carcaboso Jaume Mora Cinzia Lavarino Silvia Mateo-Lozano |
| author_sort | Eliana Gonçalves-Alves |
| collection | DOAJ |
| description | Neuroblastoma is the most common extracranial solid tumor of childhood, with heterogeneous clinical manifestations ranging from spontaneous regression to aggressive metastatic disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that senses plasmatic fluctuation in the extracellular concentration of calcium and plays a key role in maintaining calcium homeostasis. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. The activation of CaSR with cinacalcet, a positive allosteric modulator of CaSR, reduces neuroblastoma tumor growth by promoting differentiation, endoplasmic reticulum (ER) stress and apoptosis. However, cinacalcet treatment results in unmanageable hypocalcemia in patients. Based on the bias signaling shown by calcimimetics, we aimed to identify a new drug that might exert tumor-growth inhibition similar to cinacalcet, without affecting plasma calcium levels. We identified a structurally different calcimimetic, AC-265347, as a promising therapeutic agent for neuroblastoma, since it reduced tumor growth by induction of differentiation, without affecting plasma calcium levels. Microarray analysis suggested biased allosteric modulation of the CaSR signaling by AC-265347 and cinacalcet towards distinct intracellular pathways. No upregulation of genes involved in calcium signaling and ER stress were observed in patient-derived xenografts (PDX) models exposed to AC-265347. Moreover, the most significant upregulated biological pathways promoted by AC-265347 were linked to RHO GTPases signaling. AC-265347 upregulated cancer testis antigens (CTAs), providing new opportunities for CTA-based immunotherapies. Taken together, this study highlights the importance of the biased allosteric modulation when targeting GPCRs in cancer. More importantly, the capacity of AC-265347 to promote differentiation of malignant neuroblastoma cells provides new opportunities, alone or in combination with other drugs, to treat high-risk neuroblastoma patients. |
| first_indexed | 2024-03-09T10:33:48Z |
| format | Article |
| id | doaj.art-2121db4c62af42d295d1c0c320cd3e75 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T10:33:48Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2121db4c62af42d295d1c0c320cd3e752023-12-01T21:04:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238432310.3390/ijms23084323AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing HypocalcemiaEliana Gonçalves-Alves0Marta Garcia1Carlos J. Rodríguez-Hernández2Soledad Gómez-González3Rupert C. Ecker4Mariona Suñol5Oscar Muñoz-Aznar6Angel M. Carcaboso7Jaume Mora8Cinzia Lavarino9Silvia Mateo-Lozano10Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainTissueGnostics GmbH, 1020 Vienna, AustriaDepartment of Pathology, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainDevelopmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, SpainNeuroblastoma is the most common extracranial solid tumor of childhood, with heterogeneous clinical manifestations ranging from spontaneous regression to aggressive metastatic disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that senses plasmatic fluctuation in the extracellular concentration of calcium and plays a key role in maintaining calcium homeostasis. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. The activation of CaSR with cinacalcet, a positive allosteric modulator of CaSR, reduces neuroblastoma tumor growth by promoting differentiation, endoplasmic reticulum (ER) stress and apoptosis. However, cinacalcet treatment results in unmanageable hypocalcemia in patients. Based on the bias signaling shown by calcimimetics, we aimed to identify a new drug that might exert tumor-growth inhibition similar to cinacalcet, without affecting plasma calcium levels. We identified a structurally different calcimimetic, AC-265347, as a promising therapeutic agent for neuroblastoma, since it reduced tumor growth by induction of differentiation, without affecting plasma calcium levels. Microarray analysis suggested biased allosteric modulation of the CaSR signaling by AC-265347 and cinacalcet towards distinct intracellular pathways. No upregulation of genes involved in calcium signaling and ER stress were observed in patient-derived xenografts (PDX) models exposed to AC-265347. Moreover, the most significant upregulated biological pathways promoted by AC-265347 were linked to RHO GTPases signaling. AC-265347 upregulated cancer testis antigens (CTAs), providing new opportunities for CTA-based immunotherapies. Taken together, this study highlights the importance of the biased allosteric modulation when targeting GPCRs in cancer. More importantly, the capacity of AC-265347 to promote differentiation of malignant neuroblastoma cells provides new opportunities, alone or in combination with other drugs, to treat high-risk neuroblastoma patients.https://www.mdpi.com/1422-0067/23/8/4323neuroblastomacalcium-sensing receptorcalcimimeticcinacalcetAC-265347biased signaling |
| spellingShingle | Eliana Gonçalves-Alves Marta Garcia Carlos J. Rodríguez-Hernández Soledad Gómez-González Rupert C. Ecker Mariona Suñol Oscar Muñoz-Aznar Angel M. Carcaboso Jaume Mora Cinzia Lavarino Silvia Mateo-Lozano AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia International Journal of Molecular Sciences neuroblastoma calcium-sensing receptor calcimimetic cinacalcet AC-265347 biased signaling |
| title | AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia |
| title_full | AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia |
| title_fullStr | AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia |
| title_full_unstemmed | AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia |
| title_short | AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia |
| title_sort | ac 265347 inhibits neuroblastoma tumor growth by induction of differentiation without causing hypocalcemia |
| topic | neuroblastoma calcium-sensing receptor calcimimetic cinacalcet AC-265347 biased signaling |
| url | https://www.mdpi.com/1422-0067/23/8/4323 |
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