Peroxiredoxin 1 Interacts with Androgen Receptor and Enhances Its Transactivation

Park, Soo Yeon; Yu, Xiaofei; Ip, Clement; Mohler, James L.; Bogner, Paul N.; Park, Young‐Mee

doi:10.1158/0008-5472.can-07-0651

Cited by 76 publications

(84 citation statements)

References 47 publications

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“…Peroxiredoxin family members also regulate proliferation, in part through intracellular signaling cascades that apply hydrogen peroxide as a molecular second messenger. No known roles for PRDX4 have been described in the context of development, although other peroxiredoxin family members interact with the androgen receptor (AR) and modulate ARmediated signaling (44). All of the prostate cancer studies we evaluated showed elevated expression of PRDX4 in neoplastic lesions.…”

Section: Discussionmentioning

confidence: 95%

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Pritchard

Mecham²,

Dumpit³

et al. 2009

Cancer Research

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Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes.

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Section: Discussionmentioning

confidence: 95%

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Pritchard

Mecham²,

Dumpit³

et al. 2009

Cancer Research

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“…For example, Prx I interacts with the oncoprotein c-Abl to inhibit its tyrosine kinase activity (13) and regulates AKT activation through preserving PTEN activity (14). In prostate cancer cells, Prx I interacts with androgen receptor, enhances its transactivation activity, and contributes to the aggressive cancer phenotype (15). Prx II is a negative regulator of platelet-derived growth factor (PDGF) receptor-mediated cell signaling (16) and a negative regulator of nuclear factor-kappa B (NF-κB) activation in mouse fibroblasts (17).…”

Section: Discussionmentioning

confidence: 99%

Sulfiredoxin–Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling

Wei

Jiang²,

Xiao

et al. 2011

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

100

114

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Oxidative stress is known to cause tumorigenesis through induction of DNA and lipid damage. It also promotes cancer progression through a largely unknown mechanism. Sulfiredoxin (Srx) is a novel oxidative stress-induced antioxidant protein whose function in tumorigenesis and cancer progression has not been well studied. We report that Srx is highly expressed in human lung cancer. Knockdown of Srx reduces anchorage-independent colony formation, cell migration, and invasion of human lung cancer cells. Srx preferentially interacts with Peroxiredoxin (Prx) IV relative to other Prxs due to its intrinsic higher binding affinity. Knockdown of Prx IV recapitulates the phenotypic changes of depleting Srx. Disruption or enhancement of the Srx-Prx IV axis leads respectively to reduction or acceleration of tumor growth and metastasis formation in vivo. Through identification and validation of the downstream mediators we unraveled the Srx-mediated signaling network that traverses AP-1-activating and other phosphokinase signaling cascades. Our work reveals that the Srx-Prx IV axis is critical for lung cancer maintenance and metastasis, suggesting that targeting the Srx-Prx IV axis may provide unique effective strategies for cancer prevention and treatment.oncogene | signal transduction L ung cancer is the most common form of human cancer and is the leading cause of cancer mortality worldwide. Despite recent progress in early detection and combined therapeutic strategies, the overall survival rate of patients has not been significantly improved (1). Many risk factors, including the exposure to tobacco smoke, have been identified as causally related to lung carcinogenesis in patients. Tobacco smoke contains a number of carcinogens, and metabolism of these carcinogens generates active metabolites directly leading to formation of DNA adducts and the accumulation of oxygen-free radicals that induce oxidative stress that contributes significantly to tumorigenesis and cancer progression (2).Oxygen-free radicals, including reactive oxygen species (ROS) and reactive nitrogen species, have been shown to be causally related to cancer progression and metastasis. However, the molecular mechanisms of oxidative stress in cancer maintenance and metastases formation are still not well understood, due in part to the dual roles of ROS as both deleterious and beneficial species in cancer cells. Under physiological conditions ROSinduced oxidative stress response causes cellular senescence and apoptosis. Cancer cells have an enhanced defense system characterized by intrinsically higher expression of antioxidant proteins, and ROS are more likely to function as mediators of intracellular signaling cascades that are critical for maintenance of tumor phenotypes (3). Sulfiredoxin (Srx), or neoplastic progression 3, was previously identified as a differentially expressed gene with unknown function that distinguished transformed and transformation-sensitive from transformation-resistant mouse epidermal cells (4). More recent studies substantiate that Srx...

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“…Studies suggest that Prx1 may act as a molecular chaperone, and modulate the activities of growth regulatory proteins with an outcome favoring cell survival (17,20,25,26). Based on the results from a combination of mutagenesis, biochemical, and X-ray crystallographic studies, we recently reported that despite >90% homology in their amino acid sequences, human Prx1 and Prx2 proteins are structurally and functionally distinguishable (27).…”

Section: Discussionmentioning

confidence: 99%

“…Elevated Prx1 was implicated in the chemotherapy resistance of breast cancer (16) and in radiotherapy resistance of lung cancer cells (17). On the other hand, down-regulation of Prx1 was shown to sensitize lung cancer cells to radiation and reduce metastasis (18,19), and to increase the sensitivity of prostate cells to androgen ablation treatment (20). Similarly, overexpression of Prx2 rendered leukemia and stomach cancer cells resistant to various chemotherapeutic agents (21,22), whereas downregulation of Prx2 sensitized head and neck cancer cells to radiation and gastric carcinoma to cisplatin (23,24).…”

mentioning

confidence: 99%

Up-Regulation of Peroxiredoxin 1 in Lung Cancer and Its Implication as a Prognostic and Therapeutic Target

Kim¹,

Bogner²,

Baek³

et al. 2008

Clinical Cancer Research

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Purpose: Peroxiredoxin 1 and 2 are highly homologous members of the Prx (or Prdx) protein family. Prx1and Prx2 are elevated in several human cancers, and this seems to confer increased treatment resistance and aggressive phenotypes. This study was undertaken to examine the expression profiles of Prx1 and Prx2 in non^small cell lung cancer (NSCLC), and to test their prognostic value in predicting patient survival. Experimental Design: To gain insight into the regulatory mechanisms of Prx1and Prx2 expression in NSCLC, their respective transcript profiles were examined in NSCLC cell lines from the NCI-60 panel Affymetrix database sets, and the promoter compositions of the two genes were investigated using computer-based multiple sequence alignment analyses. Immunohistochemical analyses of Prx1and Prx2 were done on a total of 235 NSCLC specimens with stage I through IV disease. The expression profiles of Prx1and Prx2 in tumor specimens, and their associations with survival, were investigated. Results and Conclusion: The levels of prx1 transcript were higher than those of prx2 in NSCLC cell lines, and the upstream regulatory sequences of the two genes display striking differences. The relative risk of death increased as Prx1 expression levels increased (P = 0.036) in a multivariate Cox model, independent of other clinicopathologic variables associated with survival. No statistically significant correlation was observed between Prx2 and survival. These results suggest that Prx1 may possess unique functions and regulatory mechanisms in NSCLC which are not shared with Prx2, and that Prx1may serve as a new prognostic biomarker and therapeutic target in NSCLC.Lung cancer continues to be the leading cause of cancerrelated mortality in the United States and worldwide, with an estimated 213,380 new cases in 2007, lung cancer is expected to kill more than 160,000 Americans this year (1). Non -small cell lung cancer (NSCLC) accounts for up to 80% of all lung cancer cases and includes adenocarcinoma, squamous carcinoma, large-cell carcinoma, and mixed types. The prognosis of patients with lung cancer is poor, and the 5-year survival rate of patients with NSCLC remains among the lowest of all major human cancers at less than 15%. Studies suggest that conventional therapies may have reached a therapeutic plateau (2). The current challenge is to identify new therapeutic targets and strategies, and to incorporate them into recent treatment regimens with the goal of improving therapeutic gain.

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Peroxiredoxin 1 Interacts with Androgen Receptor and Enhances Its Transactivation

Cited by 76 publications

References 47 publications

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Sulfiredoxin–Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling

Up-Regulation of Peroxiredoxin 1 in Lung Cancer and Its Implication as a Prognostic and Therapeutic Target

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