AC-265347 inhibits neuroblastoma tumor growth by induction of differentiation without causing hypocalcemia
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ABSTRACT:
PROVIDER: PRJNA801268 | ENA |
REPOSITORIES: ENA
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Project description:Neuroblastoma is the most common extracranial solid childhood tumor with clinical manifestations ranging from benign tumors that spontaneously regress to highly aggressive metastatic disease. Unfortunately, there is no therapy known to be curative for high-risk neuroblastoma. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor 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, ER stress and apoptosis. However, these promising results came with an associated side effect, since cinacalcet exposure resulted in hypocalcemia. Based on the biased 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. Microarrays analysis suggested biased allosteric modulation of the CaSR signaling by both calcimimetics towards distinct intracellular pathways since no upregulation of genes involved in calcium signaling and ER stress were observed in 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 also up-regulated cancer testis antigens (CTAs), thus providing new opportunities for CTA-based immunotherapies. Taken together, this study helps to shed light about 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 control minimal residual disease and to prevent relapse in patients affected with neuroblastoma.
2022-04-27 | GSE195577 | GEO
Project 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.
| S-EPMC9027928 | biostudies-literature
Project description:CHD5 inhibits metastasis of neuroblastoma
| PRJNA762064 | ENA
Project description:Knockdown of METTL14 inhibits the development of neuroblastoma
| PRJNA1023971 | ENA
Project description:CaSR modulation inhibits neuroblastoma growth
2016-03-30 | GSE73506 | GEO
Project description:CaSR modulation inhibits neuroblastoma growth
2016-03-30 | GSE73504 | GEO
Project description:CaSR modulation inhibits neuroblastoma growth 8 control and 7 samples treated with CaSR allosteric activator
2016-03-30 | E-GEOD-73504 | biostudies-arrayexpress
Project description:CaSR modulation inhibits neuroblastoma growth 8 control and 8 samples treated with CaSR allosteric activator
2016-03-30 | E-GEOD-73506 | biostudies-arrayexpress
Project description:Glyceraldehyde (GA) is a 3-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. This phenomenon was extensively studied up until the 1970’s. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits cancer cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13C-labelling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in the cancer cell. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. This elucidated a specific subset of proteins harbouring oxidoreductase and antioxidant activity. Analysis of nucleotide pools in L-GA treated cells depicted a remarkable and previously unreported phenotype. Nucleotide biosynthesis in neuroblastoma cells is significantly inhibited upon L-GA treatment. Through the application of the antioxidant N-acetyl-cysteine in conjunction with L-GA, metabolic inhibition was partially relieved. We present novel evidence for the multi-modal mechanism of L-GA action in neuroblastoma cells. Specifically, a simple sugar that inhibits the growth of cancer via dysregulating the fragile homeostatic environment inherent to the cancerous cell.
2024-05-21 | PXD048695 | Pride
Project description:Single-color gene expression profiles from 3 neuroblastoma cell lines were generated using 44K oligonucleotide microarrays. To gain insights into the molecular processes occurring upon FOXP1 re-expression, we performed series of time-resolved gene expression measurements in FOXP1 and GFP transgenic neuroblastoma cell lines. Single-color gene expression profiles from 3 neuroblastoma cell lines were generated using 44K oligonucleotide microarrays. Total RNA of FOXP1- and GFP-expressing IMR-32, CHP-212 and SK-N-BE(2) cells was isolated at 0, 12, 24 and 72 h using Trizol. To determine global differences in the expression profiles of FOXP1- and GFP-induced IMR-32, CHP-212 and SK-N-BE(2) cells, mean expression levels of each gene between FOXP1-induced and control (GFP) cells were compared.
2014-10-17 | E-GEOD-62419 | biostudies-arrayexpress