Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

Iamartino, Luca; Elajnaf, Taha; Gall, Katharina; David, Jacquelina; Manhardt, Teresa; Heffeter, Petra; Grusch, Michael; Derdak, Sophia; Baumgartner‐Parzer, Sabina; Schepelmann, Martin; Kállay, Enikö

doi:10.1016/j.bbamcr.2020.118836

Cited by 11 publications

(22 citation statements)

References 67 publications

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“…To ensure proper interaction of the calcilytic with the receptor, cells were always pre-treated with NPS 2143 (or vehicle) for 30 min before their treatment with NPS 568 (if applicable). The total treatment time after the addition of NPS 568 was 4 h. Here, we used 1 µmol/L of each compound, as the initial results using NPS R- 568 and NPS R- 2143 in these transfected colon cancer cells were obtained using drug concentrations that were previously deemed to be CaSR-selective [ 5 , 9 , 14 , 15 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we needed to prove that our contradictory observation [ 9 ] that the activation of the CaSR induces IL-8 expression is real, and indeed mediated by the CaSR. The results of the Iamartino study [ 9 ] were already very convincing, as the observed upregulation of several inflammatory markers was seen only in the cells expressing the CaSR but not in the cells with undetectable CaSR levels. While the observation that R- 568 induced the expression of these markers suggested that the CaSR mediates this effect, we needed unequivocal proof.…”

Section: Discussionmentioning

confidence: 99%

“…We used lentiviral stably transduced colon cancer cell lines HT29 CaSR-GFP and HT29 GFP [ 9 ]. The parent HT-29 cell line was obtained commercially (HTB-38™) from the American Type Culture Collection (ATCC, Manassas, VA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…These transfections are necessary because colonic epithelial cells, during transformation into cancer cells, lose their native CaSR expression. As there are no reliable native colon epithelial cell lines available, we used these modified cancer cells to study the effect of the CaSR in colonic epithelial cells in vitro where we had already determined that CaSR expression and stimulation using R- 568 leads to massive changes in their gene expression pattern, including a strong upregulation of pro-inflammatory genes [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

Schepelmann

Kupper

Sladczyk

et al. 2021

IJMS

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Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

Schepelmann

Kupper

Sladczyk

et al. 2021

IJMS

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“…Animal studies have directly demonstrated inhibition of colon tumor formation with calcium [26][27][28], and in vitro studies have provided mechanistic insight into how calcium modulates epithelial growth [29]. Past studies have shown that activation of the extracellular calcium-sensing receptor (CaSR) on the epithelial cell surface is critical to growth control [21,[66][67][68]. This is of interest because several of the trace elements present in Aquamin ® , including members of the lanthanoid family, have a higher affinity for CaSR than calcium itself [69].…”

Section: Discussionmentioning

confidence: 99%

A Multi-Mineral Intervention to Modulate Colonic Mucosal Protein Profile: Results from a 90-Day Trial in Human Subjects

et al. 2021

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The overall goal of this study was to determine whether Aquamin®, a calcium-, magnesium-, trace element-rich, red algae-derived natural product, would alter the expression of proteins involved in growth-regulation and differentiation in colon. Thirty healthy human subjects (at risk for colorectal cancer) were enrolled in a three-arm, 90-day interventional trial. Aquamin® was compared to calcium alone and placebo. Before and after the interventional period, colonic biopsies were obtained. Biopsies were evaluated by immunohistology for expression of Ki67 (proliferation marker) and for CK20 and p21 (differentiation markers). Tandem mass tag-mass spectrometry-based detection was used to assess levels of multiple proteins. As compared to placebo or calcium, Aquamin® reduced the level of Ki67 expression and slightly increased CK20 expression. Increased p21 expression was observed with both calcium and Aquamin®. In proteomic screen, Aquamin® treatment resulted in many more proteins being upregulated (including pro-apoptotic, cytokeratins, cell–cell adhesion molecules, and components of the basement membrane) or downregulated (proliferation and nucleic acid metabolism) than placebo. Calcium alone also altered the expression of many of the same proteins but not to the same extent as Aquamin®. We conclude that daily Aquamin® ingestion alters protein expression profile in the colon that could be beneficial to colonic health.

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Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway

Orduña-Castillo

del-Río-Robles

García‐Jiménez

et al. 2021

J. Cell Commun. Signal.

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Calcium sensing receptor, a pleiotropic G protein coupled receptor, activates secretory pathways in cancer cells and putatively exacerbates their metastatic behavior. Here, we show that various CaSR mutants, identified in breast cancer patients, differ in their ability to stimulate Rac, a small Rho GTPase linked to cytoskeletal reorganization and cell protrusion, but are similarly active on the mitogenic ERK pathway. To investigate how CaSR activates Rac and drives cell migration, we used invasive MDA‐MB‐231 breast cancer cells. We revealed, by pharmacological and knockdown strategies, that CaSR activates Rac and cell migration via the Gβγ‐PI3K‐mTORC2 pathway. These findings further support current efforts to validate CaSR as a relevant therapeutic target in metastatic cancer.

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Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

Cited by 11 publications

References 67 publications

Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

A Multi-Mineral Intervention to Modulate Colonic Mucosal Protein Profile: Results from a 90-Day Trial in Human Subjects

Calcium sensing receptor stimulates breast cancer cell migration via the Gβγ-AKT-mTORC2 signaling pathway

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