title: Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma.
abstract: Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive and chemoresistant tumor with dismal prognosis. Most ATCs harbor mutations that activate RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. Therefore, we investigated and correlated the expression of phosphatase and tensin homolog, pERK, and pAKT proteins as well as mutations of BRAF, RAS, and p53 genes in samples of patients with ATC. Furthermore, we evaluated the potential of inhibition of these pathways on chemosensitization of ATC using 2 thyroid carcinoma cell lines (FRO and SW1736). Our results revealed a negative correlation between the activity of RAS-MAPK-ERK and PI3K-AKT-mTOR pathways in samples of patients. To be specific, the PI3K-AKT-mTOR pathway was suppressed in patients with activated NRAS or high pERK expression. In vitro results suggest that the inhibition of either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity of thyroid cancer cells to classic chemotherapeutics. This may form a basis for the development of novel genetic-based therapeutic approach for this cancer type.
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Milosevic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Pesic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Dinic
authors.affiliation: Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
authors.forename: Zorka
authors.initials: Z
authors.lastname: Milovanovic
authors.affiliation: Department of Thoracopulmonary Pathology, Clinical Centre of Serbia, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Stojsic
authors.affiliation: Institute for Oncology and Radiology of Serbia, Belgrade, Serbia; School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Radan
authors.initials: R
authors.lastname: Dzodic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Tanic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia. Electronic address: jasnam@ibiss.bg.ac.rs.
authors.forename: Jasna
authors.initials: J
authors.lastname: Bankovic
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000429:Alcohol Oxidoreductases; D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C021496:lactate-malate transhydrogenase; C546842:MTOR protein, human; C494929:PTEN protein, human