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Administration of Glucocorticoids to Ovarian Cancer Patients Is Cancer Therapy: Clinical Administration of Glucocorticoids to Ovarian Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes SGK1 and MKP1/DUSP1 in Ovarian Tissues Amal Melhem,1S. DianeYamada,2 Gini F. Fleming,1Bertha Delgado,3 Deanna R. Brickley,1Wei Wu,1 Masha Kocherginsky,4 and Suzanne D. Conzen1, 5 Abstract Purpose: To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulat- ed kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline. Experimental Design: Eighteen patientswere randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immu- nohistochemistry. SGK1 and MKP1/DUSP1 mRNA levelswere determined using quantitative real-time PCR. Results: Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, F2.6) compared with only 1.5-fold (SEM, F0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, F2.9) following dexamethasone versus 1.1-fold (SEM, F0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor. Conclusion: Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patientsthrough increasedanti-apoptotic gene expression. Although synthetic glucocorticoids have antitumor effects solid tumors have been shown (a) in vivo using human in lymphocytic malignancies, endogenous and synthetic xenografts in severe combined immunodeficiency mice, (b) glucocorticoids can promote cell survival in epithelial tumors, in vitro using tumor cell lines, and (c) ex vivo in excised primary including breast (1) and ovarian cancers (2, 3). The anti- human tumors treated in vitro with glucocorticoids followed by apoptotic effects associated with glucocorticoid treatment of chemotherapy (2). Glucocorticoids also promote cell survival in normal mouse mammary epithelium, wherein they prevent lobulo-alveolar duct involution through inhibition of apopto- Authors’ Affiliations: Departmentsof 1Medicine, 2Obstetrics and Gynecology, sis (4). In cell culture and xenograft studies, the mechanisms by 3 4 5 Pathology, Health Studies, and Ben May Department for Cancer Research,The which glucocorticoids inhibit apoptosis require changes in the University of Chicago, Chicago, Illinois Received8/15/08;revised1/13/09;accepted1/20/09;publishedOnlineFirst4/21/09. expression of genes whose protein products alter downstream Grant support: R01CA089208 (S.D. Conzen) and the pilot clinical trial and core pro- and anti-apoptotic signaling events. Until now, evidence facility funding from the University of Chicago Cancer Research Center Support that these genes are induced in patient tumors following Grant P30CA014599. glucocorticoid administration has not been reported. The costs of publication of this article were defrayed in part by the payment of page Our laboratory has done several genomewide expression charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. studies to identify and validate gene expression changes Note: Supplementary data for thisarticle are available at Clinical Cancer Research following glucocorticoid treatment of benign and malignant Online (http://clincancerres.aacrjournals.org/). mammary epithelial cells (1). Two such genes, serum and Requests for reprints: Suzanne D. Conzen, MC 2115,The University of Chicago, glucocorticoid-regulated kinase 1 (SGK1) and map kinase Chicago, IL 60637. Phone: 773-834-2604; Fax: 773-834-0188; E-mail: MKP1 @ phosphatase 1 [ ; also known as dual specificity phos- sdconzen uchicago.edu. DUSP1 F 2009 American Association for Cancer Research. phatase 1 ( )], were found to be required for anti- doi:10.1158/1078-0432.CCR-08-2131 apoptotic signaling mediated by glucocorticoids. Knockdown Clin Cancer Res 2009;15(9) May 1, 2009 3196 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2009 American Association for Cancer Research. Anti-apoptotic Gene Up-Regulation by Glucocorticoids immediately before and at specified time points after dexa- Translational Relevance methasone/normal saline administration. We found that i.v. administration of dexamethasone (20 mg) is associated with a Ovarian cancer isthe fifth leading causeof cancer rapid and significant up-regulation of the SGK1 and MKP1/ deathsin women in the United States.Glucocorticoidsare DUSP1 prosurvival gene expression in ovarian tumor tissues. widely used in conjunction with chemotherapy for ovarian These findings may have important implications for the use of cancer because they have potent anti-emetic effects and glucocorticoids in conjunction with chemotherapy and are to can prevent hypersensitivity reactions associated with our knowledge the first report of the in vivo gene expression paclitaxel therapy. However, in preclinical models, gluco- response to dexamethasone administration in human ovarian corticoid-mediated activation of the epithelial tumor tissues. cell glucocorticoid receptor is associated with decreasing chemotherapy-induced apoptosis. Here, we show for the first time that i.v. administration of dexamethasone to Materials and Methods patientsisassociated with the increased expression of two potent anti-apoptotic genes, serum and glucocorti- Study design. After obtaining University of Chicago institutional coid-regulated kinase1and map kinase phosphatase1/dual review board approval, a randomized placebo-controlled trial was specificity phosphatase 1, in ovarian tumors. Our findings done. Eighteen patients were enrolled between July 2003 and suggest that glucocorticoids may decrease chemothera- September 2007 through the Gynecologic Oncology Clinic at the py-induced apoptosis in human epithelial cancers through University of Chicago. All patients agreed to and signed an institutional review board–approved written informed consent before enrollment. the activation of anti-apoptotic signaling cascades. Principal inclusion criteria were women z18 y of age, suspected of having ovarian or primary peritoneal cancer, and scheduled for exploratory laparotomy for definitive diagnosis and debulking surgery. of either SGK1 or MKP1 using small hairpin RNA reversed the Patients who were concurrently receiving glucocorticoid treatment were cell survival afforded by glucocorticoid pretreatment (1). SGK1 excluded from the study, as were pregnant patients, diabetics, and encodes a serine/threonine kinase that was originally identified patients with an albumin of <3.0 mg/dL. The patients were randomized as a glucocorticoid-induced gene in rat mammary epithelial to receive dexamethasone 20 mg i.v. or an equivalent volume normal tumor cells (5). The exact molecular mechanisms by which saline injection, to be administered in a blinded fashion immediately glucocorticoids inhibit apoptosis remain unknown, although following the initial intra-operative biopsy. the ability of SGK1 to phosphorylate and inactivate the pro- Human tissue sample collection and storage. Intra-operative biopsies were taken from suspected gross tumor sites before the infusion of apoptotic forkhead transcription factors (6), the c-jun-NH - 2 dexamethasone or normal saline and where possible, given limitations kinases (1 and 2; ref. 7), and p27 (8) are likely important of tissue availability and operative time, at 30 min, 2 h, and 4 h after mechanisms. In addition, a fraction of SGK1 localizes to the infusion. These time points were designed to capture the peak predicted mitochondrial membrane and endoplasmic reticulum (9, 10), induction of SGK1 and MKP1/DUSP1 mRNA based on in vitro cell wherein it may be involved in the regulation of membrane culture data (15, 16); surgery was not prolonged to obtain tumor potential during apoptotic stress. Furthermore, the catalytic samples at the later time points, and therefore, most patients only had domain of SGK is 55% homologous to the protein kinase B two collection points. In the operating room, the tissue samples were (Akt) kinase domain (5), suggesting that SGK1 may play a role immediately placed in a plastic cassette, submerged in Optimum in cancer. Indeed, SGK1 has been shown to be overexpressed in Cutting Temperature embedding media (Tissue-Tec), snap frozen in a substantial proportion of cancers, including breast (11) and liquid nitrogen, and transported in a portable liquid nitrogen tank
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