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MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer

BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKCß and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) re...

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Autores principales: Faoro, Leonardo, Cervantes, Gustavo M., Ferguson, Benjamin D., Seiwert, Tanguy Y., Yala, Soheil, Vigneswaran, Wicki T., Westerhoff, Maria, Tretiakova, Maria S., Ferguson, Mark K., Moura, Glaci L., Husain, Aliya N., Vokes, Everett E., Salgia, Ravi
Formato: Texto
Lenguaje:English
Publicado: Medknow Publications 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791827/
https://www.ncbi.nlm.nih.gov/pubmed/19955662
http://dx.doi.org/10.4103/1477-3163.57857
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author Faoro, Leonardo
Cervantes, Gustavo M.
Ferguson, Benjamin D.
Seiwert, Tanguy Y.
Yala, Soheil
Vigneswaran, Wicki T.
Westerhoff, Maria
Tretiakova, Maria S.
Ferguson, Mark K.
Moura, Glaci L.
Husain, Aliya N.
Vokes, Everett E.
Salgia, Ravi
author_facet Faoro, Leonardo
Cervantes, Gustavo M.
Ferguson, Benjamin D.
Seiwert, Tanguy Y.
Yala, Soheil
Vigneswaran, Wicki T.
Westerhoff, Maria
Tretiakova, Maria S.
Ferguson, Mark K.
Moura, Glaci L.
Husain, Aliya N.
Vokes, Everett E.
Salgia, Ravi
author_sort Faoro, Leonardo
collection PubMed
description BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKCß and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) respectively. MATERIALS AND METHODS: Patient samples were analyzed by immunohistochemistry for expression of PKCß and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKCß and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKCß was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3ß) were evaluated by immunoblotting. Statistical analysis was performed using SPSS 16.0. RESULTS: Expression of MET positively correlated with lymph node metastases (p=.0004), whereas PKCß showed no correlation (p=0.204). MET and PKCß expression were also strongly correlated (p<0.001). Expression of MET was observed in 5/8 cell lines (H358, H1703, A549, H1993, H2170; absent from H522, H661, or SW1573), whereas PKCß expression was observed in 8/8 cell lines. Cell proliferation was significantly impaired by treatment with SU11274 and enzastaurin, and their effects were synergistic in combination (CI=0.32 and 0.09). Phosphorylation of MET, FAK, AKT, and GSK3ß were strongly inhibited with both agents in combination. CONCLUSIONS: Concomitant inhibition of MET and PKCß significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted.
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spelling pubmed-27918272009-12-11 MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer Faoro, Leonardo Cervantes, Gustavo M. Ferguson, Benjamin D. Seiwert, Tanguy Y. Yala, Soheil Vigneswaran, Wicki T. Westerhoff, Maria Tretiakova, Maria S. Ferguson, Mark K. Moura, Glaci L. Husain, Aliya N. Vokes, Everett E. Salgia, Ravi J Carcinog Original Article BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKCß and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) respectively. MATERIALS AND METHODS: Patient samples were analyzed by immunohistochemistry for expression of PKCß and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKCß and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKCß was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3ß) were evaluated by immunoblotting. Statistical analysis was performed using SPSS 16.0. RESULTS: Expression of MET positively correlated with lymph node metastases (p=.0004), whereas PKCß showed no correlation (p=0.204). MET and PKCß expression were also strongly correlated (p<0.001). Expression of MET was observed in 5/8 cell lines (H358, H1703, A549, H1993, H2170; absent from H522, H661, or SW1573), whereas PKCß expression was observed in 8/8 cell lines. Cell proliferation was significantly impaired by treatment with SU11274 and enzastaurin, and their effects were synergistic in combination (CI=0.32 and 0.09). Phosphorylation of MET, FAK, AKT, and GSK3ß were strongly inhibited with both agents in combination. CONCLUSIONS: Concomitant inhibition of MET and PKCß significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted. Medknow Publications 2009-11-24 /pmc/articles/PMC2791827/ /pubmed/19955662 http://dx.doi.org/10.4103/1477-3163.57857 Text en © 2009 Faoro http://creativecommons.org/licenses/by/2.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Faoro, Leonardo
Cervantes, Gustavo M.
Ferguson, Benjamin D.
Seiwert, Tanguy Y.
Yala, Soheil
Vigneswaran, Wicki T.
Westerhoff, Maria
Tretiakova, Maria S.
Ferguson, Mark K.
Moura, Glaci L.
Husain, Aliya N.
Vokes, Everett E.
Salgia, Ravi
MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title_full MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title_fullStr MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title_full_unstemmed MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title_short MET/PKCß expression correlate with metastasis and inhibition is synergistic in lung cancer
title_sort met/pkcß expression correlate with metastasis and inhibition is synergistic in lung cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791827/
https://www.ncbi.nlm.nih.gov/pubmed/19955662
http://dx.doi.org/10.4103/1477-3163.57857
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