Prx I Suppresses K-ras-Driven Lung Tumorigenesis by Opposing Redox-Sensitive ERK/Cyclin D1 Pathway

Park, Young Ho; Kim, Sun Uk; Lee, Bo Kyoung; Kim, Hyun Sun; Song, In Sung; Shin, Hye Jun; Han, Ying; Chang, Kyu Tae; Kim, Jin Man; Lee, Dong Seok; Kim, Yeul Hong; Choi, Chang; Kim, Bo Yeon; Yu, Dae Yeul

doi:10.1089/ars.2011.4421

Cited by 51 publications

(59 citation statements)

References 54 publications

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“…In addition, Nrf2 also significantly increased in accordance with increased expression of Prx I. Furthermore, Nrf2 bound to the Prx I promoter region to regulate Prx I gene expression, as reported in lung cancer cells [11, 26]. Like Nrf2, FoxM1 also significantly increased in accordance with increased expression of Prx I in H-Ras G12V HCC cells.…”

Section: Discussionsupporting

confidence: 58%

Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis

et al. 2016

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Peroxiredoxin I (Prx I), an antioxidant enzyme, has multiple functions in human cancer. However, the role of Prx I in hepatic tumorigenesis has not been characterized. Here we investigated the relevance and underlying mechanism of Prx I in hepatic tumorigenesis. Prx I increased in tumors of hepatocellular carcinoma (HCC) patients that aligned with overexpression of oncogenic H-ras. Prx I also increased in H-rasG12V transfected HCC cells and liver tumors of H-rasG12V transgenic (Tg) mice, indicating that Prx I may be involved in Ras-induced hepatic tumorigenesis. When Prx I was knocked down or deleted in HCC-H-rasG12V cells or H-rasG12V Tg mice, cell colony or tumor formation was significantly reduced that was associated with downregulation of pERK pathway as well as increased intracellular reactive oxygen species (ROS) induced DNA damage and cell death. Overexpressing Prx I markedly increased Ras downstream pERK/FoxM1/Nrf2 signaling pathway and inhibited oxidative damage in HCC cells and H-rasG12V Tg mice. In this study, we found Nrf2 was transcriptionally activated by FoxM1, and Prx I was activated by the H-rasG12V/pERK/FoxM1/Nrf2 pathway and suppressed ROS-induced hepatic cancer-cell death along with formation of a positive feedback loop with Ras/ERK/FoxM1/Nrf2 to promote hepatic tumorigenesis.

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Section: Discussionsupporting

confidence: 58%

Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis

et al. 2016

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“…Our data confirmed the results of previous studies on cellular and animal NSCLC models regarding interrelationship of these two oncogenes. It was shown that KRAS knockdown in both A549 and NCI-H358 cells decreased the levels of cyclin D1 expression compared with control groups [31], while persistent exposure of mouse epithelial cells to nicotine stimulated RAS signaling, and subsequently increased cyclin D1 promoter activity and its protein expression [32]. Additionally, analysis of alterations in cell cycle regulatory genes in bitransgenic mouse model that inducibly expressed the human mutant KRAS allele showed no change in cyclin D1 RNA expression, while increased staining for cyclin D1 was detected [33].…”

Section: Discussionmentioning

confidence: 98%

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.

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“…Also, PTEN null mouse embryonic fibroblasts are resistant to ROS mediated induction of Prx1/Prx2 expression [81]. Prx1 may also be required for the ROS mediated activation of the K-Ras/ERK pathway that contributes to lung tumorigenesis [82]. Moreover, Prx1 along with Prx4 play essential roles in the regulation of c-Jun and AP-1 mediated promoter activity in lung cancer cells [83], and activation of Prx1 by histone deacetylase inhibitor FK228 result in induction of apoptosis in esophageal tumor cells [84].…”

Section: The Srx-prx Axis In Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

Mishra¹,

Jiang²,

Wu³

et al. 2015

Cancer Letters

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Redox signaling is a critical component of cell signaling pathways that is involved in regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Peroxiredoxin (Prx) is a family of thiol-based peroxidases that acts as a regulator of redox signaling. Members of Prx family can act as antioxidants and chaperone. Sulfiredoxin (Srx) is an antioxidant protein that exclusively reduces over-oxidized typical 2-Cys Prx. Srx have different affinities for individual Prx and it also catalyzes deglutathionylation of variety of substrates. Individual components of Srx-Prx system play critical roles in carcinogenesis by modulating cell signaling pathway involved in cell proliferation, migration and metastasis. Expression levels of individual components of Srx-Prx axis has been correlated with patient survival outcome in multiple cancer types. This review will summarize the molecular basis of differences in affinity of Srx for individual Prx and the role of individual components of Srx-Prx system in tumor progression and metastasis. This enhanced understanding of molecular aspects of Srx-Prx interaction and its role in cell signal transduction will help in defining Srx-Prx system as a future therapeutic target in human cancer.

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Prx I Suppresses K-ras-Driven Lung Tumorigenesis by Opposing Redox-Sensitive ERK/Cyclin D1 Pathway

Abstract: These findings provide a better understanding of oxidative stress-mediated lung tumorigenesis.

Cited by 51 publications

References 54 publications

Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis

Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

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