Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis
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.
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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)
- et al.
The multiple roles of PTEN in tumor suppression
Cell
(2000) - et al.
Activation of the PI3K/Akt pathway and chemotherapeutic resistance
Drug Resist Updat
(2002) - et al.
The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
J Biol Chem
(1998) - et al.
Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN
Cell
(1998) - et al.
Structure, regulation and function of PKB/AKT—a major therapeutic target
Biochim Biophys Acta
(2004) - et al.
Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor
Cell
(1999) - et al.
PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway
J Biol Chem
(1999) - et al.
Loss of expression of the pten gene protein product is associated with poor outcome in breast cancer
Mod Pathol
(2001) - American cancer society surveillance research. Cancer facts and figures 2004. Atlanta (GA): American cancer society;...
- et al.
The phosphatidylinositol 3-kinase AKT pathway in human cancer
Nat Rev Cancer
(2002)
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
Protein kinase B(c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation
Biochem J
New insights into tumor suppression: PTEN suppression tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
PNAS
Immunohistochemical demonstration of phospho-akt in high gleason grade prostate cancer
Clin Cancer Res
Studies of apurinic/apyrimidinic endonuclease/ref-1 expression in epithelial ovarian cancer: correlations with tumor progression and platinum resistance
Clin Cancer Res
Pten is essential for embryonic development and tumor suppression
Nat Genet
Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants
Cell Death Differ
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trasuzumab, or tamoxifen in breast cancer cells
Mol Cancer Ther
Altered protein kinase C(PKC) isoforms in non-small cell lung cancer cells: PKC delta promotes cellular survival and chemotherapeutic resistance
Cancer Res
Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression
Mol Cell Biol
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