Association of p53 and mdm2 in the development and progression of non-small cell lung cancer

Javid, Jamsheed; Mir, Rashid; Pk, Julka; Ray, P. C.; Saxena, Alpana

doi:10.1007/s13277-015-3208-6

Cited by 16 publications

(14 citation statements)

References 20 publications

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“…Both LUSC and LUAD tumors had approximately equal frequencies of gains for the MDM2 gene (16.5% and 19.2%, respectively), consistent with previous reports (see Supporting Information Figure S4).…”

Section: Resultssupporting

confidence: 90%

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Qiu

Gazdar

et al. 2017

Genes Chromosomes & Cancer

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The accurate classification of non-small cell lung carcinoma (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is essential for both clinical practice and lung cancer research. Although the standard WHO diagnosis of NSCLC on biopsy material is rapid and economic, more than 13% of NSCLC tumors in the USA are not further classified. The purpose of this study was to analyze the genome-wide pattern differences in copy number variations (CNVs) and to develop a CNV signature as an adjunct test for the routine histopathologic classification of NSCLCs. We investigated the genome-wide CNV differences between these two tumor types using three independent patient datasets. Approximately half of the genes examined exhibited significant differences between LUAD and LUSC tumors and the corresponding non-malignant tissues. A new classifier was developed to identify signature genes out of 20 000 genes. Thirty-three genes were identified as a CNV signature of NSCLC. Using only their CNV values, the classification model separated the LUADs from the LUSCs with an accuracy of 0.88 and 0.84, respectively, in the training and validation datasets. The same signature also classified NSCLC tumors from their corresponding non-malignant samples with an accuracy of 0.96 and 0.98, respectively. We also compared the CNV patterns of NSCLC tumors with those of histologically similar tumors arising at other sites, such as the breast, head, and neck, and four additional tumors. Of greater importance, the significant differences between these tumors may offer the possibility of identifying the origin of tumors whose origin is unknown.

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Section: Resultssupporting

confidence: 90%

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Qiu

Gazdar

et al. 2017

Genes Chromosomes & Cancer

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“…To answer this question, Sullivan et al analysed genome-wide shRNA screening data from HCT116 colorectal cancer cells [29], and we analysed similar data from MCF-7 breast cancer cells [24], in combination with transcriptomic data. p53 is a promising therapeutic target in lung cancer treatment due to its frequent malfunction in human lung cancers, which is closely correlated with poor clinical outcomes in NSCLC patients [20]. Although Sullivan et al also performed genome-wide shRNA screening in A549 lung carcinoma cells, no transcriptomic data from A549 cells treated with p53-reactivating compounds are currently available.…”

Section: Discussionmentioning

confidence: 99%

“…The most common mechanism underlying p53 dysfunction in human cancers is p53 dysregulation induced by the amplification of its negative regulators, such as the MDM2 and MDM4 (encoding MDMX) genes [19]. A recent study determined that the MDM2 309 T > G polymorphism is one of the most important factors associated with p53 downregulation and poor clinical outcomes in NSCLC patients; thus, this polymorphism may represent a promising target with respect to NSCLC treatment at the molecular level [20]. However, a study investigating the antitumour activities of the small-molecule MDM2 inhibitor RG7388 in lung cancer models observed only p53 pathway activation and cell proliferation inhibition, but not p53-mediated apoptosis [21].…”

Section: Introductionmentioning

confidence: 99%

Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells

Zhang¹,

Zhu²,

Sun³

et al. 2017

Cell Physiol Biochem

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Background/Aims: p53 dysfunction is frequently observed in lung cancer. Although restoring the tumour suppressor function of p53 is recently approved as a putative strategy for combating cancers, the lack of understanding of the molecular mechanism underlying p53-mediated lung cancer suppression has limited the application of p53-based therapies in lung cancer. Methods and Results: Using RNA sequencing, we determined the transcriptional profile of human non-small cell lung carcinoma A549 cells after treatment with two p53-activating chemical compounds, nutlin and RITA, which could induce A549 cell cycle arrest and apoptosis, respectively. Bioinformatics analysis of genome-wide gene expression data showed that distinct transcription profiles were induced by nutlin and RITA and 66 pathways were differentially regulated by these two compounds. However, only two of these pathways, 'Adherens junction' and 'Axon guidance', were found to be synthetic lethal with p53 re-activation, as determined via integrated analysis of genome-wide gene expression profile and short hairpin RNA (shRNA) screening. Further functional protein association analysis of significantly regulated genes associated with these two synthetic lethal pathways indicated that GSK3 played a key role in p53-mediated A549 cell apoptosis, and then gene function study was performed, which revealed that GSK3 inhibition promoted p53-mediated A549 cell apoptosis in a p53 post-translational activity-dependent manner. Conclusion: Our findings provide us with new insights regarding the mechanism by which p53 mediates A549 apoptosis and may cast light on the development of more efficient p53-based strategies for treating lung cancer.

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“…MDM2 was considered as an oncoprotein and elevated MDM2 was frequently occurred in human lung tumor tissues . In the tumor cells without p53 mutation, p53, the tumor suppressor, was often inactivated by some mechanisms, such as overexpression of its negative regulator MDM2 .…”

Section: Discussionmentioning

confidence: 99%

“…was frequently occurred in human lung tumor tissues. 18 In the tumor cells without p53 mutation, p53, the tumor suppressor, was often inactivated by some mechanisms, such as overexpression of its negative regulator MDM2. 19 It had been proven that MDM2/p53 axis was widely regarded as an attractive therapeutic target in a broad range of tumors, including SCLC.…”

Section: Mdm2 Was Considered As An Oncoprotein and Elevated Mdm2mentioning

confidence: 99%

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

Shi

2019

The Kaohsiung J of Med Scie

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The proto‐oncogene MDM2 is a nuclear‐localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti‐infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small‐cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl‐2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti‐SCLC activity by suppressing MDM2 expression, which suggested that anti‐infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.

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Association of p53 and mdm2 in the development and progression of non-small cell lung cancer

Cited by 16 publications

References 20 publications

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

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