COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma

Erkanli, Serkan; Bolat, Fılız; Kayaselçuk, Fazi̇let; Demirhan, Beyhan; Kuşçu, Esra

doi:10.1016/j.ygyno.2006.08.044

Cited by 58 publications

(53 citation statements)

References 29 publications

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“…This suggests that survivin overexpression is selective toward high-grade, poorly differentiated tumors. This finding is consistent with reverse transcriptase PCR and immunohistochemistry data from other laboratories (Lehner et al, 2002;Takai et al, 2002;Erkanli et al, 2006Erkanli et al, , 2007.…”

supporting

confidence: 92%

DNA methylation inhibits p53-mediated survivin repression

2009

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The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the reexpression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

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supporting

confidence: 92%

DNA methylation inhibits p53-mediated survivin repression

2009

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“…Previous studies have shown a positive correlation between increased Survivin expression and endometrial carcinoma tumor grade (27,28). We found that Survivin transcript abundance significantly decreased in all endometrial cancer cell lines that had an apoptotic response to DCA.…”

Section: Discussionsupporting

confidence: 56%

Dichloroacetate induces apoptosis in endometrial cancer cells

Wong

Huggins

Debidda

et al. 2008

Gynecologic Oncology

189

170

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Purpose-A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism.Methods-A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca 2+ , and mitochondrial membrane potential were examined to assess apoptotic mechanism.Results-Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on noncancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest Statement:The authors declare there are no conflicts of interest. NIH Public Access

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“…Increased Cox-2 expression could be due to increased P-AKT expression in intraepithelial neoplastic glands found in ugePTENARKO uterus as previous studies in human endometrial cancer cells (St-Germain et al 2004) and hepatocellular carcinoma cells (Leng et al 2003) reported positive correlation between P-AKT and Cox-2 expression. Furthermore, previous clinical studies have reported overexpression of uterine Cox-2 in patients with EMC (Erkanli et al 2007, Nasir et al 2007). However, Cox-1 that is involved in cell signaling and maintains tissue homeostasis was not affected by uterine-specific PTEN or AR knockout in our study.…”

Section: :5mentioning

confidence: 92%

“…However, Cox-1 that is involved in cell signaling and maintains tissue homeostasis was not affected by uterine-specific PTEN or AR knockout in our study. Cox-1 has been shown to be expressed in most tissues, and its expression is not altered by cytokines and growth factors (Erkanli et al 2007). However, further analysis of Cox gene expression (i.e., immunohistochemistry) in the uterus is required to localize its expressions in different uterine cell types to further clarify a possible role of Cox pathway in the present murine uterine carcinogenesis model.…”

Section: :5mentioning

confidence: 99%

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

Choi

Zheng

Handelsman

et al. 2016

Endocrine-Related Cancer

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Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n = 8) and ugeARKO (n = 7) uteri. Uterine weight was significantly (P = 0.002) increased in ugePTENARKO (374 ± 97 mg (mean ± s.e.)) compared with WT (97 ± 6 mg), ugeARKO (94 ± 12 mg), and ugePTENKO (205 ± 33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.Correspondence should be addressed to D J Handelsman

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COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma

Cited by 58 publications

References 29 publications

DNA methylation inhibits p53-mediated survivin repression

DNA methylation inhibits p53-mediated survivin repression

Dichloroacetate induces apoptosis in endometrial cancer cells

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

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