Glucocorticoids Inhibit Cell Death in Ovarian Cancer and Up-regulate Caspase Inhibitor cIAP2

Abstract

Purpose: Almost all patients with epithelial ovarian cancer receive chemotherapy and, concurrently, the synthetic steroid hormone dexamethasone to alleviate the side effects. This study aims to test the impact of steroid hormones on the apoptosis of epithelial ovarian cancer cells and to identify its mediators. Experimental Design: Tumor cell lines from 19 patients with advanced epithelial ovarian cancer were analyzed for glucocorticoid receptor, estrogen receptor, progesterone receptor, and androgen receptor expression. Cells were incubated with corresponding steroid hormones at serumequivalent doses in hormone-depleted medium. Apoptosis was induced by application of tumor necrosis factor^related apoptosis-inducing ligand or staurosporine and determined by poly(ADPribose)polymerase cleavage and cell survival. Microarray with 8K cDNA chips including apoptosisrelevant genes was used to study genes regulated by glucocorticoids. Results: In cell culture, tumor necrosis factor^related apoptosis-inducing ligand^induced apoptosis in OV-MZ-30 and OV-MZ-31 cells was reduced after treatment with dexamethasone or cortisol, but not with estradiol, progesterone, or androstenedione. Microarray analysis revealed a 7-fold up-regulation of the caspase inhibitor cIAP2 by dexamethasone in OV-MZ-30 and OV-MZ-31 cells. cIAP2 up-regulation by glucocorticoids was confirmed by RT-PCR and Western blot analysis in OV-MZ-30, OV-MZ-31, OV-CAR3, and SK-OV-3 cells. Down-regulation of cIAP2 expression by small interfering RNA sensitized SK-OV-3 cells to apoptosis inducer staurosporine. Under clinical conditions, treatment with dexamethasone was associated with significant up-regulation of cIAP2 in the ascites cells. Conclusions: Activation of the glucocorticoid receptor in epithelial ovarian cancer cells caused an antiapoptotic effect associated with the enhanced cellular expression level of cIAP2. Dexamethasone pretreatment of epithelial ovarian cancer patients receiving apoptosis-inducing chemotherapy raises questions about a negative effect on antitumor efficacy.Plasma levels of steroid hormones such as estrogens, androgens, progesterone, and the cellular expression level of the corresponding hormone receptors can be factors promoting the development of several solid tumors including ovarian and breast cancer (1 -3). The expression of the estrogen receptor in breast cancer is a well-known example and its pharmacologic inhibition by (selective) antiestrogens is extensively studied for breast cancer treatment as well as for its prevention (4, 5). Less is known about the impact of steroid hormones on the development of ovarian cancer. Contradictory studies on hormone replacement therapy regarding ovarian cancer risk have been presented (6, 7).Besides sex hormone receptors, the glucocorticoid receptor is another steroid hormone receptor with an effect on cancer cells. The synthetic glucocorticoid dexamethasone has been shown to increase resistance to chemotherapeutic drugs and radiation therapy in cells from solid cancer (8 -12). Thi...

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

“…Resistance to apoptosis accompanied by uncontrollable cell division could promote growth of tumor mass in the nude mice. This working model is also supported by the knowledge that a G 2 /M checkpoint defect promotes tumorigenesis (3) and that there is close association of up-regulation of three such antiapoptotic proteins, Bcl-xL, XIAP, and cIAP2, with constitutive activation of NF-B and resistance to apoptosis in a variety of human malignancies (45)(46)(47)(48)(49)(50).…”

Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells

“…Recently, more and more data from preclinical studies, and to some extent from clinical studies, have strongly recommended a GC-conferred resistance to cancer therapy in the majority of malignant solid tumors -irrespective of tumor origin and the nature of specific anticancer drugs (Wolff et al 1996, Weller et al 1997, Webster et al 2002, Herr et al 2003, Wu et al 2004, Gassler et al 2005, Runnebaum & Brüning 2005, Sui et al 2006, Zhang et al 2006a,b,c,d,e, 2007. In this study, we have demonstrated that Dex could protect human ovarian IgG (10 µg/ml) Anti-β1 (µg/ml) Figure 4 Dex-enhanced cell attachment and cell survival are partially reversed by integrin b1-blocking antibody.…”

“…Recent studies suggest that GC-conferred cellular resistance to cancer therapy may occur through multiple mechanisms, for example, by enhancing DNA repair capacity, suppressing host anti-tumor immune responses, and blocking apoptosis (Rutz 2002, Herr et al 2003, Rutz & Herr 2004. Some dexamethasone (Dex)-induced proteins, such as the inhibitors of apoptosis (cIAP-2, X-IAP, Bcl-XL, and Bcl-2), mitogen-activated protein kinase phosphatase-1, as well as GC-induced serum, and GC-inducible kinase-1 (SGK-1) may contribute to the prevention of chemotherapy-induced apoptosis by GCs (Webster et al 2002, Herr et al 2003, Wu et al 2004, Runnebaum & Brüning 2005). However, the molecular mechanisms underlying the anti-apoptotic effect of GCs in epithelial cells are still largely unknown.…”

Novel Genomic Effects of Glucocorticoids in Epidermal Keratinocytes

“…GCs are known inducers of apoptosis in numerous cell types, including thymocytes, eosinophils, neutrophils, hippocampal neurons, and proliferative chondrocytes (56 -60), and various malignancies of lymphoid origin and thus have become one of the most common therapeutic agents for leukemias and lymphomas (61). Interestingly, GCs have been described to exert an anti-apoptotic effect on epithelial ovarian or breast cancer cells, human glioblastoma, hepatoma, and fibroblasts (62)(63)(64)(65)(66). The antiapoptotic effect of GCs on keratinocytes is achieved through the concerted suppression of pro-apoptotic and induction of anti-apoptotic genes.…”