Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells

Khodarev, Nikolai N.; Minn, Andy J.; Efimova, Elena V.; Darga, Thomas E.; Labay, Edwardine; Beckett, Michael A.; Mauceri, Helena J.; Roizman, Bernard; Weichselbaum, Ralph R.

doi:10.1158/0008-5472.can-07-1019

Cited by 120 publications

(168 citation statements)

References 51 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…Moreover, ISG15 was identified as a p53 target gene (Polyak et al, 1997). This is in line with a recent report coupling the sensitivity to IFN to DNA damage (Khodarev et al, 2007;Desai et al, 2008). In addition, the chemotherapy-mediated ISG15 induction required a functional p53 protein (Liu et al, 2004), which is also expressed by LNCaP cells.…”

Section: Discussionsupporting

confidence: 87%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

View full text Add to dashboard Cite

The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, ARdependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR þ androgensensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

show abstract

Section: Discussionsupporting

confidence: 87%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Here, we show that these genes are highly inducible by ROS and regulated by STAT1. STAT1 had been traditionally viewed as a mere IFN signal transducer but has recently been linked with aggressiveness, therapy resistance, and oxidative stress responses of several cancers (49,50). Consistently, we prove that the coordinated expression of MMP-1, ADI-POR1, and DTX3L fosters the invasive and proliferative phenotype of Ewing tumors.…”

Section: Discussionsupporting

confidence: 78%

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Grünewald

Diebold

Espósito

et al. 2012

Molecular Cancer Research

111

132

View full text Add to dashboard Cite

Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1. Mol Cancer Res; 10(1); 52-65. Ó2011 AACR.

show abstract

“…Using the same approaches, we found that activation of a STAT1-dependent pathway mediates resistance to radiation treatment and predicts response to adjuvant chemotherapy and radiation in breast cancer patients (30)(31)(32). Thus, these approaches have allowed the identification of biologically relevant and differentially expressed pathways in experimental models.…”

Section: Discussionmentioning

confidence: 97%

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

Pitroda

Khodarev

Beckett

et al. 2009

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

Self Cite

100

View full text Add to dashboard Cite

The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in human breast cancers. Although MUC1 modulates the activity of estrogen receptor ␣ (ER), there is no information regarding the effects of MUC1 on global gene expression patterns and the potential role of MUC1-induced genes in predicting outcome for breast cancer patients. We have developed an experimental model of MUC1-induced transformation that has identified the activation of genes involved in cholesterol and fatty acid metabolism. A 38-gene set of experimentally derived MUC1-induced genes associated with lipid metabolism was applied to the analysis of ER ؉ breast cancer patients treated with tamoxifen. The results obtained from 2 independent databases demonstrate that patients overexpressing MUC1 and the lipid metabolic pathways are at significantly higher risk for death and recurrence/distant metastasis. By contrast, these genes were not predictive in untreated patients. Furthermore, a positive correlation was found between expression of the 38-gene set and the ER signaling pathway. These findings indicate that (i) MUC1 regulates cholesterol and fatty acid metabolism, and (ii) activation of these pathways in ER ؉ breast cancers predicts failure to tamoxifen treatment.breast cancer ͉ expression profiling ͉ lipid metabolism ͉ cholesterol biosynthesis ͉ risk factors

show abstract

Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells

Abstract: Elsewhere, we reported that multiple serial in vivo passage of a squamous cell carcinoma cells

Cited by 120 publications

References 51 publications

Expression, regulation and function of the ISGylation system in prostate cancer

Expression, regulation and function of the ISGylation system in prostate cancer

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment

Contact Info

Product

Resources

About