Elsevier

Lung Cancer

Volume 51, Issue 2, February 2006, Pages 181-191
Lung Cancer

Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis

https://doi.org/10.1016/j.lungcan.2005.10.003Get rights and content

Summary

Akt, a downstream mediator of phosphatidylinositol 3-kinase (PI3K), is a signal transduction protein that plays a central role in tumorigenesis. The tumor suppressor gene PTEN negatively regulates the PI3K/Akt signaling pathway. However, the roles of Akt and PTEN function in patients with non-small cell lung cancer (NSCLC) is not well established. To clarify roles of expression of phosphorylated Akt (p-Akt) and loss of PTEN expression in biological behavior and prognosis of NSCLC. Immunohistochemical staining was used to determine the expression of p-Akt and PTEN in 20 cases of normal lung tissues and 102 cases patients with NSCLC. All patients with NSCLC were followed from 3 to 60 months. The positive incidence of p-Akt expression and loss incidence of PTEN expression in NSCLC were 41.2% (42/102) and 46.1% (47/102), while negative of p-Akt expression (0%, 0/20) and positive of PTEN expression (100%, 20/20) in normal lung tissues. Overexpression of p-Akt and loss of PTEN expression were correlated to poor differentiation, lymph node involvement, distant metastasis and late stages. A significant negative correlation was observed between expression of p-Akt and PTEN (r = −0.425, P < 0.001). Patients with p-Akt positive expression (42/102) and loss of PTEN expression (47/102) showed significantly worse 5 years survival rate and median survival time than relevant those with p-Akt negative expression (14.29% versus 33.33%, 14 months versus 32 months, Log-rank test X2 = 14.24, P < 0.001) and PTEN positive expression (10.64% versus 38.18%, 15 months versus 40 months, Log-rank test X2 = 21.06, P < 0.001). A univariate analysis revealed that smoking, tumor size, lymph node involvement, distant metastasis, stage, p-Akt and loss of PTEN expression were significant correlative factors with prognosis. The result of multivariate Cox analysis showed that smoking, stage and loss of PTEN expression were independent prognosticators. p-Akt is overexpressed and accompanied by the loss of PTEN in clinical specimens of NSCLC. Both p-Akt and PTEN are concerned with invasion and metastasis of NSCLC. Loss of PTEN expression is an independent poor prognostic factor for patients with NSCLC.

Introduction

Lung cancer is one of the leading causes of cancer mortality in both men and women, and its incidence is increasing all over the world. Lung cancer mortality has consistently been higher than the combined mortality of breast, colon, and prostate cancers. The 5-years survival rate all stages of lung cancer is only 15% [1], and this situation has not improved for 30 years. Non-small cell lung cancer (NSCLC) comprises over 75% of lung cancers diagnosed. The long-term survival rate of patients remains unsatisfactory with NSCLC due to unclear pathological mechanism. Thus, there is an urgent need for further understanding the molecular mechanisms of NSCLC and finding new molecular targets for treatment.

Activation of the intracellular prosurvival signal transduction protein Akt, also known as protein kinase B, has been proposed as a central signaling event in carcinogenesis [2] and has been shown in experimental models to confer resistance to chemotherapy and radiation [3]. Akt is activated by phosphatidylinositol 3 phosphates, the products of phosphatidylinositol 3 phosphates kinase (PI3K) [4]. In addition, Akt activity is commonly dysregulated in a variety of human tumors because of frequent inactivation of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene, which negatively regulates phosphatidylinositol 3 phosphate levels [5] and alterations of this gene have been identified in a large fraction of cancers including lung cancer [6]. Thus, we have postulated here that the loss of PTEN function with subsequent activation of PI3K/Akt signaling pathway contributes to carcinogenesis. However, the roles of Akt and PTEN in patients with NSCLC have not been well established. In order to study the expression of phosphorylated Akt (p-Akt) and PTEN and their correlation with biological behavior and prognosis of NSCLC, we examined the expression of p-Akt and PTEN in 102 cases paraffin-embedded tissue specimens of NSCLC.

Section snippets

Patients

102 patients who underwent resection of NSCLC were selected for the study. They underwent surgery at the Peking University People's Hospital and Beijing Tuberculosis and Thoracic Tumor Research Institute from January 1997 to December 1998. Table 1 summarizes the characteristics of the 102 resected NSCLCs. The patients consisted of 73 males and 29 females ranging from 30 to 78 years (median, 59 years) of age. All patients gave informed consent before collection of the specimens. Institutional

p-Akt and PTEN protein expression in normal and malignant lung tissues

p-Akt was primarily cytoplasmic and, less frequently, nuclear, however, PTEN was primarily nuclear and, less frequently, cytoplasmic (Fig. 1G and H). We detected p-Akt expression in 0 of 20 (0%) and PTEN expression in 20 of 20 (100%) in normal lung specimens, and p-Akt expression in 42 of 102 (41.2%) and loss of PTEN expression in 47 of 102 (46.1%) NSCLC specimens (Fig. 1A–H). Compared to normal lung specimens, the increased frequency of p-Akt expression in NSCLC specimens was statistically

Discussion

A growing body of evidence in the basic science literatures implicates that Akt is a cytosolic signal transduction protein that figures prominently in mechanisms of carcinogenesis and chemoresistance [3], [10], [11], [12], [13]. These studies have been performed on animal tissues or human lung cancer cell lines. PTEN is a lipid phosphatase dephosphorylating the 3-position of phosphatidylinositol 3,4,5-triphosphate, a second messenger of PI3K [6], [14]. PTEN antagonizes PI3K activity and

Conclusions

In summary, we have demonstrated that overexpression of p-Akt is accompanied by the loss of PTEN in clinical specimens of NSCLC. Both p-Akt and PTEN are concerned with invasion and metastasis of NSCLC. Our data indicated p-Akt expression and loss of PTEN expression confer poor prognosis in NSCLC, but PTEN is an independent prognostic factor for patients with NSCLC. Restoring the imbalance of Akt and PTEN may become a new target to treat NSCLC.

Conflicts of interest

Our study has no conflict of interest.

Acknowledgment

We thank Mr. Jie Chen for his assistance with the data analysis.

References (41)

  • J. Brognard et al.

    Akt/protein kinase B is constitutively active in non-small cell lung cancer and promotes cellular survival and resistance to chemotherapy and radiation

    Cancer Res

    (2001)
  • P.J. Coffer et al.

    Protein kinase B(c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

    Biochem J

    (1998)
  • L.C. Cantley et al.

    New insights into tumor suppression: PTEN suppression tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway

    PNAS

    (1999)
  • S.N. Malik et al.

    Immunohistochemical demonstration of phospho-akt in high gleason grade prostate cancer

    Clin Cancer Res

    (2002)
  • S. Freitas et al.

    Studies of apurinic/apyrimidinic endonuclease/ref-1 expression in epithelial ovarian cancer: correlations with tumor progression and platinum resistance

    Clin Cancer Res

    (2003)
  • A. Di Cristofano et al.

    Pten is essential for embryonic development and tumor suppression

    Nat Genet

    (1998)
  • J. Brognard et al.

    Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

    Cell Death Differ

    (2002)
  • A.S. Clark et al.

    Constitutive and inducible Akt activity promotes resistance to chemotherapy, trasuzumab, or tamoxifen in breast cancer cells

    Mol Cancer Ther

    (2002)
  • A.S. Clark et al.

    Altered protein kinase C(PKC) isoforms in non-small cell lung cancer cells: PKC delta promotes cellular survival and chemotherapeutic resistance

    Cancer Res

    (2003)
  • J. Hutchinson et al.

    Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression

    Mol Cell Biol

    (2001)
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