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Doctoral Thesis
DOI
10.11606/T.23.2007.tde-02012008-151120
Document
Author
Full name
Flavia Sirotheau Corrêa Pontes
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2007
Supervisor
Committee
Pinto Júnior, Décio dos Santos (President)
Kataoka, Maria Sueli da Silva
Mesquita, Ricardo Alves de
Sousa, Suzana Cantanhede Orsini Machado de
Wisniewski, Ana Carolina Thomé Capuano
Title in Portuguese
Avaliação in vitro da expressão das proteínas PTEN, Akt, Mdm2 e p53 em células de carcinoma epidermóide de cabeça e pescoço submetidas a ação de EGF e 17-AAG
Keywords in Portuguese
17-AAG
Akt
Carcinoma epidermóide
EGF
Mdm2
p53
PTEN
Abstract in Portuguese
O carcinoma epidermóide de cabeça e pescoço é responsável por 90% das neoplasias malignas, nesta região. Molecularmente, inúmeras vias de sinalização, ainda não muito bem compreendidas, são responsáveis pelo seu crescimento e invasão para tecidos vizinhos, além de metástases para órgãos distantes. Este trabalho destinou-se a avaliar o crosstalk entre as vias de sinalização do PTEN, Akt, Mdm2 e p53 em quatro linhagens de células de carcinoma epidermóide (HN6, HN19, HN30 e HN31) e queratinócitos imortalizados (HaCat), estimulados com EGF (fator de crescimento epitelial) e 17-AAG. Para observar a localização e os níveis de PTEN, Akt, Mdm2 e p53 nos diferentes compartimentos celulares estas proteínas foram localizadas e quantificadas no interior celular através das técnicas de imunofluorescência e western blot, respectivamente. Os resultados mostraram que a ativação da via do PI3K/Akt, pelo EGF, promoveu a proliferação celular, sendo HN31 a linhagem celular de melhor resposta proliferativa. Quando as células foram tratadas com 17-AAG a linhagem HN31 foi a que melhor traçou um perfil apoptótico com diminuição dos níveis de Akt, ausência de Mdm2 e aumento dos níveis de PTEN e p53. As linhagens celulares HN6 e HN19 continuaram apresentando níveis significativos de Akt e Mdm2, o que sugere um potencial mais agressivo devido a manutenção do comportamento proliferativo e anti-apoptótico destas linhagens.
Title in English
In vitro evaluation of the expression of PTEN protein, Akt, Mdm2 and p53 in cells of squamous cell carcinoma of head and neck under the action of EGF and 17-AAG
Keywords in English
17-AAG
Akt
EGF
HNSCC
Mdm2
p53
PTEN
Abstract in English
Head and neck squamous cell carcinoma (HNSCC) represents 90% of all head and neck malignancies. Cancer growth, invasion and metastasis are due to several signaling pathways that, unfortunately, are not completely understood. The aim of this study was the crosstalk evaluation among PTEN, Akt, Mdm2 and p53 signaling pathways in four different HNSCC cell lines (HN6, HN19, HN30 and HN31) and HaCat cell line (immortalized keratinocytes), all of than treated with 10ng/ml EGF (epidermal growth factor) and 2?M 17-AAG. Western blot and imunofluorescence were performed in order to analyze PI3K/Akt signaling key target proteins: PTEN, Akt, Mdm2 and p53. Treatment of HNSCC cell lines with EGF resulted in activation of the PI3K/Akt pathway and enhanced cell proliferation. The results showed higher proliferative activity in HN31 cell line. The treatment of HNSCC cell lines with 17-AAG inhibited the proliferation in various levels. HN31 cell lines expressed PTEN and p53 in high levels and low expression for Akt and Mdm2 proteins. These findings suggest that 17-AAG can induce p53-dependent apoptosis in HN31 cell lines. On the contrary, HN6 and HN19 cell lines displayed high levels of Akt and Mdm2 proteins, resulting in decreased apoptosis and increased aggressive potential.
 
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Publishing Date
2008-03-31
 
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