RESUMO
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 Gßγ-PI3K-mTORC2 pathway. These findings further support current efforts to validate CaSR as a relevant therapeutic target in metastatic cancer.
RESUMO
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.