RAF-1 promotes survival of thyroid cancer cells harboring RET/PTC1 rearrangement independently of ERK activation

Thyroid cancer (TC) is frequently associated with BRAF or RAS oncogenic mutations and RET/PTC rear-rangements, with aberrant RAF-MEK-ERK and/or PI3K pathway activation. BRAF underlies ERR activation in most TC cells, but not in TPC-1 cells with RET/PTC1 rearrangement. Here, we show that depletion of RAF-1, a RAF family member with a poorly defined role in TC, decreases proliferation and increases apoptosis in TPC-1 cells and, less significantly, in cells harboring a BRAF(V600E) or HRAS(G13R) mutations, but without affecting ERR activation. We further demonstrate that constitutive activation of ERKs in TPC-1 cells is not caused by mutations in 50 oncogenes and tumor suppressors prone to activate the ERR pathway, or affected by inhibition of BRAF, MEK1/2 or PI3K. Our data indicate that RAF-1 is important for the survival of TPC-1 cells independently of the classical MEK1/2-ERK activation, offering new perspectives on RET/PTC signaling and for the therapy of thyroid cancers. (C) 2015 Elsevier Ireland Ltd. All rights reserved.This work was supported by the Portuguese Foundation for Science and Technology (FCT) I.P. through the strategic funding UID/BIA/04050/2013, projects PEst-C/SAU/LA0003/2013 and FCTANR/BEX-BCM/0175/2012, as well as fellowships to L. Castro (SFRH/BD/93589/2013), S. Alves (SFRH/BD/64695/2009) and S. Chaves (SFRH/BPD/89980/2012). This work was also supported by FEDER through POFC - COMPETE. Further funding was obtained from the project "Microenvironment, metabolism and cancer" that was partially supported by Programa Operacional Regional do Norte (ON.2 - O Novo Norte) under the Quadro de Referencia Estrategico Nacional (QREN) and the Fundo Europeu de Desenvolvimento Regional (FEDER). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT.