RAF-1 promotes survival of thyroid cancer cells harboring RET/PTC1 rearrangement independently of ERK activation. (5th November 2015)

• Record Type: Journal Article
• Authors: Castro, Lisandra; Alves, Sara; Chaves, Susana R.; Costa, José Luis; Soares, Paula; Preto, Ana
• Is Part Of: Molecular and cellular endocrinology. Volume 415(2015)
• Page Start: 64
• Page End: 75
• Publication Date: 2015-11-05
• Subjects: Thyroid cancer -- RAF-1 -- BRAF -- RET/PTC1 -- PI3K-AKT -- ERK; AKT V-AKT murine thymoma viral oncogene -- ATC anaplastic thyroid cancer -- BRAF V-RAF murine sarcoma viral oncogene homolog B -- BrdU 5-bromo-2-deoxyuridine -- ERK Extracellular-signal-regulated kinase -- FITC Fluorescein isothiocyanate -- FTC Follicular thyroid cancer -- GAB GRB2-associated binder -- MAPK Mitogen-activated protein kinase -- MEK Mitogen-activated protein kinase kinase -- mTOR1 Mammalian target of rapamycin 1 -- MTC medullary thyroid cancer -- PI3K Phosphatidylinositol 3 kinase -- PTC papillary thyroid cancer -- RAF1 V-raf-1 murine leukemia viral oncogene homolog -- RET/PTC1 Rearranged during transfection in papillary thyroid cancer type 1 -- RSK p90 ribosomal S6 kinase -- SRB Sulforhodamine B -- siRNA Small interfering RNA -- TSC2 Tuberous sclerosis complex 2 -- TUNEL Terminal dUTP Nick-End Labeling; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.08.006
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Thyroid cancer (TC) is frequently associated with BRAF or RAS oncogenic mutations and RET/PTC rearrangements, with aberrant RAF-MEK-ERK and/or PI3K pathway activation. BRAF underlies ERK 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 ERK 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 ERK 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. Highlights: The role of RAF-1 in thyroid cancer cell survival depends on the genetic background. Thyroid cancer cells with RET/PTC1 bypass RAF-1 or BRAF for ERK activation. RAF-1 might constitute a good molecular target in thyroid cancers with RET/PTC1.