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, S. Diane Yamada, Gini F. Fleming, Bertha Delgado, Deanna R. Brickley, Wei Wu, Masha Kocherginsky, Suzanne D. Conzen

Research output: Contribution to journalArticle

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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-regulated 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 patients were 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 immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were 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, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) 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 patientst hrough increased anti-apoptotic gene expression.

Original languageEnglish (US)
Pages (from-to)3196-3204
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number9
DOIs
StatePublished - May 1 2009
Externally publishedYes

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Dual Specificity Phosphatase 1
Mitogen-Activated Protein Kinase Kinases
Ovarian Neoplasms
Glucocorticoids
Dexamethasone
Genes
Neoplasms
Glucocorticoid Receptors
Drug Therapy
Messenger RNA
Up-Regulation
Gene Expression
serum-glucocorticoid regulated kinase
Laparotomy
Real-Time Polymerase Chain Reaction
Histology
Research Design
Anesthesia
Immunohistochemistry
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues. / Melhem, Amal; Yamada, S. Diane; Fleming, Gini F.; Delgado, Bertha; Brickley, Deanna R.; Wu, Wei; Kocherginsky, Masha; Conzen, Suzanne D.

In: Clinical Cancer Research, Vol. 15, No. 9, 01.05.2009, p. 3196-3204.

Research output: Contribution to journalArticle

Melhem, Amal ; Yamada, S. Diane ; Fleming, Gini F. ; Delgado, Bertha ; Brickley, Deanna R. ; Wu, Wei ; Kocherginsky, Masha ; Conzen, Suzanne D. / Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 9. pp. 3196-3204.
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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-regulated 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 patients were 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 immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were 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, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) 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 patientst hrough increased anti-apoptotic gene expression.",
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T1 - Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues

AU - Melhem, Amal

AU - Yamada, S. Diane

AU - Fleming, Gini F.

AU - Delgado, Bertha

AU - Brickley, Deanna R.

AU - Wu, Wei

AU - Kocherginsky, Masha

AU - Conzen, Suzanne D.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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-regulated 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 patients were 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 immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were 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, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) 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 patientst hrough increased anti-apoptotic gene expression.

AB - 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-regulated 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 patients were 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 immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were 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, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) 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 patientst hrough increased anti-apoptotic gene expression.

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