Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer Journal Article

   

Authors:	Yoshizawa, A.; Fukuoka, J.; Shimizu, S.; Shilo, K.; Franks, T. J.; Hewitt, S. M.; Fujii, T.; Cordon-Cardo, C.; Jen, J.; Travis, W. D.
Article Title:	Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer
Abstract:	Purpose: The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non-small cell lung carcinoma (NSCLC). Experimental Design: The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. Results: Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6-positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). Conclusions: This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC. ©2010 AACR.
Keywords:	immunohistochemistry; signal transduction; mitogen activated protein kinase; protein kinase b; cancer survival; controlled study; human tissue; protein phosphorylation; survival rate; overall survival; cancer growth; phenotype; gene overexpression; cluster analysis; gene expression; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; phosphorylation; prediction; gene activation; mammalian target of rapamycin; tuberin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; initiation factor 4e; mitogen activated protein kinase 1; mitogen activated protein kinase 3; tissue array analysis; ras protein; tissue microarray; mitogen activated protein kinase kinase; eukaryotic initiation factor-4e; mitogen-activated protein kinase 3; protein s6
Journal Title:	Clinical Cancer Research
Volume:	16
Issue:	1
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2010-01-01
Start Page:	240
End Page:	248
Language:	English
DOI:	10.1158/1078-0432.ccr-09-0986
PUBMED:	20008839
PROVIDER:	scopus
PMCID:	PMC7581274
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-74949114784&partnerID=40&md5=9d30e20160464465a0194183206f86a8
Notes:	--- - "Cited By (since 1996): 10" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus"

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