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

Tang, Jianmin; He, Quan-ying; Guo, Ruixia; Chang, Xiaona

doi:10.1016/j.lungcan.2005.10.003

Cited by 298 publications

(272 citation statements)

References 24 publications

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“…p-Akt plays a central role in processes of tumorigenesis (36), and its levels have prognostic value in lung cancer (37). The retinoic acid receptor is a direct substrate of Akt (38) and cyclin-dependent kinase (39,40).…”

Section: Discussionmentioning

confidence: 99%

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Patlolla

Biddick

et al. 2013

Cancer Prevention Research

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Lung cancer is the leading cause of cancer-related deaths. b-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 mmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 b-escin) or 36 weeks (15 control, 5 b-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm b-escin significantly suppressed lung tumor (adenoma þ adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. b-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to b-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of b-escin (0-40 mmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that b-escin inhibits tobacco carcinogeninduced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling. Cancer Prev Res; 6(10);

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Section: Discussionmentioning

confidence: 99%

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Patlolla

Biddick

et al. 2013

Cancer Prevention Research

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“…Tissue microarray studies on tumor samples from patients with NSCLC suggested p-Akt overexpression as an independent prognostic indicator and patients with increased p-Akt had a significant survival disadvantage compared to patients with lower Akt phosphorylation, while p53 or Ki-67 were not statistically significant prognostic indicators. 46 A recent study by Tang et al 47 showed by comparing immuno-histochemical staining in normal versus lung cancer samples that overexpression of p-AKT and loss of PTEN expression in lung cancer patients is a poor prognostic indicator and correlates with poor differentiation and metastasis. Current studies are underway to better understand the mechanism of action of HMBA on the Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

Dey¹,

Wong²,

Kua³

et al. 2008

Cell Cycle

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Hexamethylene Bisacetamide (HMBA) is a hybrid polar compound originally developed as a differentiation inducing agent. We show in this study that HMBA can inhibit activation of several NFκB target genes in both lung and breast cancer cell lines. Furthermore, consistent with its ability to inhibit NFκB function, HMBA can also sensitize cells to apoptosis. We show that HMBA mediates inhibition of the Akt and ERK/MAPK cascade, both of which are critical for cell survival and proliferation and are well known regulators of NFκB activation. We also show that PTEN negative breast cancer cells which have hyper activation of the PI3K/Akt pathway show increased sensitivity to growth inhibitory effects of combination of HMBA and TNFα. Furthermore, HMBA can decrease the kinase activity of the IKK complex leading to defective phosphorylation of IκBα and Ser536 of p65. This study gives mechanistic insight into the mechanism of action of HMBA, provides the rationale for the potential use of HMBA in combination with various existing kinase inhibitors in combination therapy and also suggests useful biomarkers for monitoring tumor response to HMBA.

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“…These genes were also upregulated in almost all recurrent tumours analysed making them interesting targets for therapeutic strategies. AKT is a serine/ threonine kinase acting as a signal transduction protein and downstream mediator of phosphatidylinositol-3-kinase (PI3K) that plays a central role in tumour progression and influences prognosis in several cancers (Lim et al, 2005;Tang et al, 2006). The oncogenic pathway PI3K/AKT plays a central role in epithelial -mesenchymal transition, a critical feature in cancer invasion and metastasis by reducing intercellular adhesion and increasing cancer cell motility (Larue and Bellacosa, 2005).…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of cervical cancer progression

Hagemann

Božanović²,

Hooper

et al. 2007

Br J Cancer

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Most cancer patients die of metastatic or recurrent disease, hence the importance to identify target genes upregulated in these lesions. Although a variety of gene signatures associated with metastasis or poor prognosis have been identified in various cancer types, it remains a critical problem to identify key genes as candidate therapeutic targets in metastatic or recurrent cancer. The aim of our study was to identify genes consistently upregulated in both lymph node micrometastases and recurrent tumours compared to matched primary tumours in human cervical cancer. Taqman Low-Density Arrays were used to analyse matched tumour samples, obtained after laser-capture microdissection of tumour cell islands for the expression of 96 genes known to be involved in tumour progression. Immunohistochemistry was performed for a panel of up-and downregulated genes. In lymph node micrometastases, most genes were downregulated or showed expressions equal to the levels found in primary tumours. In more than 50% of lymph node micrometastases studied, eight genes (AKT, BCL2, CSFR1, EGFR1, FGF1, MMP3, MMP9 and TGF-b) were upregulated at least two-fold. Some of these genes (AKT and MMP3) are key regulators of epithelial -mesenchymal transition in cancer. In recurrent tumours, almost all genes were upregulated when compared to the expression profiles of the matched primary tumours, possibly reflecting their aggressive biological behaviour. The two genes showing a consistent downregulated expression in almost all lymph node metastases and recurrent tumours were BAX and APC. As treatment strategies are very limited for metastatic and recurrent cervical cancer, the upregulated genes identified in this study are potential targets for new molecular treatment strategies in metastatic or recurrent cervical cancer.

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

Cited by 298 publications

References 24 publications

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

Molecular profiling of cervical cancer progression

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