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 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.
CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Lisandra
L
Castro
CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Sara
S
Alves
CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Susana R
SR
Chaves
IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Dr. Roberto Frias, 4200-465 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Pathology and Oncology, Medical Faculty of the University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
José Luis
JL
Costa
IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Dr. Roberto Frias, 4200-465 Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Pathology and Oncology, Medical Faculty of the University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal. Electronic address: psoares@ipatimup.pt.
Paula
P
Soares
CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Dr. Roberto Frias, 4200-465 Porto, Portugal.
Ana
A
Preto
D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D020935:MAP Kinase Signaling System; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism
D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; D019908:Proto-Oncogene Proteins c-raf
BRAF; ERK; PI3K-AKT; RAF-1; RET/PTC1; Thyroid cancer