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Sci Rep. 2019 Mar 13;9(1):4390. doi: 10.1038/s41598-019-40818-w.

The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors.

Author information

1
Unit of Internal Medicine and Endocrinology, ICS Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors and Chair of Endocrinology University of Pavia, 27100, Pavia, Italy.
2
PHD course in Experimental Medicine, University of Pavia, 27100, Pavia, Italy.
3
Molecular Cardiology, ICS-Maugeri, 27100, Pavia, Italy.
4
Department of Biopharmaceutics and Clinical Pharmacy, The University of Jordan, Amman, 11937, Jordan.
5
Department of General and Minimally Invasive Surgery, ICS Maugeri I.R.C.C.S, Pavia, 27100, Italy.
6
Division of Endocrinology and Metabolism IRCCS Istituto Auxologico Italiano, 20149, Milan, Italy.
7
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56124, Italy.
8
Department of Clinical Sciences and Community Health, University of Milan, Milano, 20122, Italy.
9
Unit of Internal Medicine and Endocrinology, ICS Maugeri I.R.C.C.S., Laboratory for Endocrine Disruptors and Chair of Endocrinology University of Pavia, 27100, Pavia, Italy. luca.chiovato@icsmaugeri.it.

Abstract

CXCL8 is a chemokine secreted by normal and thyroid cancer cells with proven tumor-promoting effects. The presence of BRAFV600E mutation is associated with a more aggressive clinical behavior and increased ability to secrete CXCL8 by papillary-thyroid-cancer cells. Aim of this study was to test the effect of the BRAF-inhibitor (PLX4720) on the basal and TNF-α-induced CXCL8 secretions in BRAFV600E mutated (BCPAP, 8305C, 8505C), in RET/PTC rearranged (TPC-1) thyroid-cancer-cell-lines and in normal-human-thyrocytes (NHT). Cells were incubated with increasing concentrations of PLX4720 alone or in combination with TNF-α for 24-hours. CXCL8 concentrations were measured in the cell supernatants. PLX4720 dose-dependently inhibited the basal and the TNF-α-induced CXCL8 secretions in BCPAP (F: 14.3, p < 0.0001 for basal and F: 12.29 p < 0.0001 for TNF-α), 8305C (F: 407.9 p < 0.0001 for basal and F: 5.76 p < 0.0001 for TNF-α) and 8505C (F:55.24 p < 0.0001 for basal and F: 42.85 p < 0.0001 for TNF-α). No effect was found in TPC-1 (F: 1.8, p = 0.134 for basal; F: 1.6, p = 0.178 for TNF-α). In NHT an inhibitory effect was found only at the highest concentration of PLX4720 (F: 13.13 p < 0.001 for basal and F: 2.5 p < 0.01 for TNF-α). Cell migration assays showed that PLX4720 reduced both basal and CXCL8-induced cell migration in BCPAP, 8305C, 8505C and NHT but not in TPC-1 cells. These results constitutes the first demonstration that PLX4720 is able to inhibit the secretion of CXCL8 in BRAFV600E mutated thyroid cancer cells indicating that, at least some, of the anti-tumor activities of PLX4720 could be exerted through a lowering of CXCL8 in the thyroid-cancer-microenvironment.

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