title: Calcium-sensing-receptor (CaSR) controls IL-6 secretion in metastatic breast cancer MDA-MB-231 cells by a dual mechanism revealed by agonist and inverse-agonist modulators.
abstract: IL-6 is a tightly controlled pleiotropic cytokine with hormone-like properties whose levels are frequently altered in cancer and inflammatory diseases. In highly invasive MDA-MB-231 breast cancer cells, basal activity of endogenously expressed calcium sensing receptor (CaSR) promotes IL-6 secretion. Interestingly, upon agonist stimulation, CaSR reduces IL-6 levels whereas it promotes secretion of various other cytokines and growth factors, raising intriguing questions about how CaSR signaling modulates IL-6 secretion. Here, using NPS-2143, which acted as an inverse agonist, we show that IL-6 secretion promoted by constitutive activity of CaSR is mechanistically linked to Gαs/PKC, MEK1/2 and mTORC1 signaling pathways, integrated by transactivated EGFR. On the other hand, agonist-stimulated CaSR engages in a Rab11a-dependent trafficking pathway critical to inhibit constitutive IL-6 secretion via the PI3K/AKT and PKC signaling pathways. These results support the emerging potential of CaSR as a therapeutic target in metastatic breast cancer whose pharmacological modulation would reduce IL-6.
authors.affiliation: Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Hernández-Bedolla
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Erika
authors.initials: E
authors.lastname: González-Domínguez
authors.affiliation: Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Cesar
authors.initials: C
authors.lastname: Zavala-Barrera
authors.affiliation: Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Tania Yareli
authors.initials: TY
authors.lastname: Gutiérrez-López
authors.affiliation: Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Joseline Janai
authors.initials: JJ
authors.lastname: Hidalgo-Moyle
authors.affiliation: Department of Pharmacology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Vázquez-Prado
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
authors.affiliation: Department of Cell Biology, Centro de Investigación y Estudios Avanzados del IPN, Apartado postal 14-740, México, D.F., 07360, Mexico. Electronic address: greyesc@cinvestav.mx.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Reyes-Cruz
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D054314:Drug Inverse Agonism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008954:Models, Biological; D009281:Naphthalenes / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015850:Interleukin-6; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing
keywords: Breast cancer; CaSR; Cell signaling; GPCR; IL-6-secretion; Traffic