Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression

Massion, Pierre P.; Taflan, Peter M.; Shyr, Yu; Rahman, S.M. Jamshedur; Yıldız, Pınar; Shakthour, Bashar; Edgerton, Mary E.; Ninan, Matthew; Andersen, Jeremiah J.; González, Adriana

doi:10.1164/rccm.200404-487oc

Cited by 123 publications

(83 citation statements)

References 33 publications

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“…In addition, the prognostic significance of AKT phosphorylation in NSCLC has resulted in conflicting results as well: in some studies AKT activation as measured by S473 phosphorylation occurs in most NSCLC and predicts for poor prognosis, 12 whereas in another report S473 phosphorylated AKT protein expression has apparently no prognostic significance. 40 In addition, the finding that there may be different prognostic roles for the various AKT isoforms (AKT1-3) 41 or even the two activating AKT residues (T308 and S473, respectively) 42 contributes to make the issue more complex.…”

Section: Discussionmentioning

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

126

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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Section: Discussionmentioning

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

126

127

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“…[40][41][42][43] Bcl-2 protects cells from apoptosis by a variety of apoptotic stimuli, regulates cell cycle, migration and gene expression. 44,45 On the other hand, signaling through the phosphatidylinositol 3-kinase (PI3-kinase) pathway results in the phosphorylation of Akt at serine 473 and/or threonine 308.…”

Section: Discussionmentioning

confidence: 99%

Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium

Wang

Dakir

Naizhen

et al. 2007

Laboratory Investigation

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The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas. KEYWORDS: achaete-scute homolog 1; apoptosis; bronchiolization of alveoli; lung; mouse model; preneoplasia; proliferation Lung cancer is the leading cause of cancer deaths in both men and women in the United States. The 5-year survival rate has remained low (15%), because the disease is generally detected at advanced and disseminated stage. 1 Contributing to the late diagnosis is the fact that precursor lesions for most lung cancer types are poorly understood. We have previously shown that the deletion of achaete-scute homolog-1 (ASH1, ASCL1), a proneural transcription factor, highly expressed in lung neuroendocrine (NE) cancers leads to the absence of pulmonary NE cells (PNECs), potential progenitors for NE cancers. 2 Constitutive expression of human ASH1 (hASH1) in the airway epithelium, on the other hand, results in epithelial proliferation and metaplasia suggesting a preneoplastic phenotype.ASH1 belongs to a diverse family of transcriptional regulators involved in fetal development and cancer that utilize the evolutionarily conserved basic helix-loop-helix (bHLH) motif. 3 Murine ASH1 (mASH1) plays a critical role in the development of the brain and the diffuse NE system including adrenal medullary chromaffin cells, thyroid parafollicular C cells, glomus chief cells and PNECs, 2,4-8 potential progenitors for small cell lung cancer (SCLC). During neurogenesis mASH1 expression is confined to mitotically active precursors where it is involved in the early stages o...

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“…The best studied oncogenes of this amplicon include phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (3,4), TP63 (5), sex-determining region Y box 2 (SOX2) (6), epithelial cell transforming 2 (ECT2) (7), and protein kinase C, iota (PRKCI) (8). In an effort to identify oncogenic drivers in lung cancer associated the 3q26-29 amplicon, we previously integrated genomic and gene expression analysis of multiple lung SCC datasets and identified Fragile X-related 1 (FXR1) as a potential new candidate driver gene (9).…”

mentioning

confidence: 99%

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Qian

Hassanein

Hoeksema

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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111

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Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

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Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression

Cited by 123 publications

References 33 publications

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

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

Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

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