PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer

Lim, Wan Teck; Zhang, W. H.; Miller, C. R.; Watters, James; Gao, Fei; Viswanathan, Avinash; Govindan, Ramaswamy; McLeod, Howard L.

doi:10.3892/or.17.4.853

Cited by 53 publications

(78 citation statements)

References 22 publications

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“…Our data are corroborated by Lim et al (30) in NSCLC, as well as by studies on breast (43), renal cell (44) and urothelial bladder (45) carcinomas. In this context, it has been hypothesised that in cancer, PTEN loss activates the Rho family proteins, leading to increased cell migration and invasion through pathways independent of AKT (43,46).…”

Section: Discussionsupporting

confidence: 80%

“…For example, rapamycin has been shown to induce the phosphorylation of AKT and eIF4E, which was suppressed by a PI3K inhibitor (50). To the best of our knowledge, although there are a few studies investigating the prognostic significance of the PI3K/p-AKT/ mTOR pathway in NSCLC (18)(19)(20)(21)(22)(23)(26)(27)(28)(29)(30)(31)(32), the prognostic utility of p-4E-BP1 expression in this regard has not been documented thus far.…”

Section: Discussionmentioning

confidence: 94%

“…On the basis of this experimental evidence, it is not surprising that much effort has been devoted to the investigation of the expression profiles of various components of the PI3K/AKT/ mTOR pathway in NSCLC (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), sometimes yielding inconsistent results. In particular, a comprehensive analysis of all components of this pathway, along with the PIK3CA, K-RAS, AKT1 and PTEN mutational status has not been performed thus far.…”

Section: Introductionmentioning

confidence: 99%

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A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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Abstract. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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“…10,11 Loss of PTEN expression occurs frequently in lung cancer and represents an independent poor prognostic factor for patients with NSCLC. 12,13 PTEN expression is reduced or lost in a high fraction of NSCLC (55% to 74%), though neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein expression in NSCLC. 14,15 Mutations of the PTEN gene in patients with NSCLC have been reported in 8% to 17% of Supported by grants from the Associazione Italiana Ricerca sul Cancro to G.V.…”

mentioning

confidence: 99%

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Amodio

Scrima²,

Palaia

et al. 2010

The American Journal of Pathology

127

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Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n ‫؍‬ 98; P < 0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).

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“…Previous studies have implicated the AKT/mTOR pathway in a diverse range of cancers including prostate (Kremer et al, 2006), lung (Lim et al, 2007), pancreas (Asano et al, 2005), colon (Nozawa et al, 2007) and oesophagus (Hou et al, 2007). Tumours that display AKT hyperactivity have shown increased sensitivity to the growth inhibitory effects of rapamycin (Neshat et al, 2001).…”

mentioning

confidence: 99%

Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma

et al. 2008

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We previously reported that tumour-associated caveolin-1 is a potential biomarker in renal cell carcinoma (RCC), whose overexpression predicts metastasis following surgical resection for clinically confined disease. Much attention has recently focused on the AKT/mTOR pathway in a number of malignancies, including RCC. Since caveolin-1 and the AKT/mTOR signalling cascade are independently shown to be important regulators of tumour angiogenesis, we hypothesised that caveolin-1 interacts with the AKT/ mTOR pathway to drive disease progression and metastasis in RCC. The aims of this study were to determine (i) the expression status of the activated AKT/mTOR pathway components (phosphorylated forms) in RCC and (ii) their prognostic value when combined with caveolin-1. Immunohistochemistry for caveolin-1, pAKT, pmTOR, pS6 and p4E-BP1 was performed on tissue microarrays from 174 clinically confined RCCs. Significantly decreased mean disease-free survival was observed when caveolin-1 was coexpressed with either pAKT (2.95 vs 6.14 years), pmTOR (3.17 vs 6.28 years), pS6 (1.45 vs 6.62 years) or p4E-BP1 (2.07 vs 6.09 years) than when neither or any one single biomarker was expressed alone. On multivariate analysis, the covariate of 'caveolin-1/AKT' (neither alone were influential covariates) was a significant influential indicator of poor disease-free survival with a hazard ratio of 2.13 (95% CI: 1.15 -3.92), higher than that for vascular invasion. Tumours that coexpressed caveolin-1 and activated mTOR components were more likely to be larger, higher grade and to show vascular invasion. Our results provide the first clinical evidence that caveolin-1 cooperates with an activated AKT/mTOR pathway in cancer and may play an important role in disease progression. We conclude that evaluation of the 'caveolin-1/AKT/mTOR axis' in primary kidney tumours will identify subsets of RCC patients who require greater postoperative surveillance and more intensive treatment.

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PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer

Cited by 53 publications

References 22 publications

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma

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