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

Akihiko Yoshizawa, Junya Fukuoka, Shigeki Shimizu, Konstantin Shilo, Teri J. Franks, Stephen M. Hewitt, Takeshi Fujii, Carlos Cordon-Cardo, Jin Jen, William D. Travis

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2010

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Eukaryotic Initiation Factors
S 6
Non-Small Cell Lung Carcinoma
Survival
Sirolimus
Staining and Labeling
Phenotype
MAP Kinase Signaling System
Cluster Analysis
Research Design
Multivariate Analysis
Antibodies
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yoshizawa, A., Fukuoka, J., Shimizu, S., Shilo, K., Franks, T. J., Hewitt, S. M., ... Travis, W. D. (2010). Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clinical Cancer Research, 16(1), 240-248. https://doi.org/10.1158/1078-0432.CCR-09-0986

Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. / Yoshizawa, Akihiko; Fukuoka, Junya; Shimizu, Shigeki; Shilo, Konstantin; Franks, Teri J.; Hewitt, Stephen M.; Fujii, Takeshi; Cordon-Cardo, Carlos; Jen, Jin; Travis, William D.

In: Clinical Cancer Research, Vol. 16, No. 1, 01.01.2010, p. 240-248.

Research output: Contribution to journalArticle

Yoshizawa, A, Fukuoka, J, Shimizu, S, Shilo, K, Franks, TJ, Hewitt, SM, Fujii, T, Cordon-Cardo, C, Jen, J & Travis, WD 2010, 'Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer', Clinical Cancer Research, vol. 16, no. 1, pp. 240-248. https://doi.org/10.1158/1078-0432.CCR-09-0986
Yoshizawa, Akihiko ; Fukuoka, Junya ; Shimizu, Shigeki ; Shilo, Konstantin ; Franks, Teri J. ; Hewitt, Stephen M. ; Fujii, Takeshi ; Cordon-Cardo, Carlos ; Jen, Jin ; Travis, William D. / Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 1. pp. 240-248.
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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.",
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AU - Yoshizawa, Akihiko

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AU - Shimizu, Shigeki

AU - Shilo, Konstantin

AU - Franks, Teri J.

AU - Hewitt, Stephen M.

AU - Fujii, Takeshi

AU - Cordon-Cardo, Carlos

AU - Jen, Jin

AU - Travis, William D.

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N2 - 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.

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