Inhibitory Effects of 17β-Estradiol and Progesterone on Ovarian Carcinoma Cell Proliferation: A Potential Role for Inducible Nitric Oxide Synthase

Bechtel, Marta K.; Bonavida, Benjamin

doi:10.1006/gyno.2001.6221

Cited by 42 publications

(32 citation statements)

References 30 publications

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“…The reports that Pg induces apoptosis in malignant mesothelioma cells 40 as well as in normal breast cells and various cancer cell lines 41 further support this view. Furthermore, in agreement with the results presented here, the role of Pg in the induction of apoptosis via induction of NOSII to increase NO levels was shown in ovarian cancer cells, 30 indicating a general function of Pg in this mechanism. In fact, several randomised studies and clinical trials have shown that treatment with progestogens led to significant though modest improvement of the relapse-free survival, 42,43 and that inclusion of progestogens in hormone replacement therapy reduces the risk of recurrence, which is associated with an increase in the apoptosis/proliferation ratio within the tumour.…”

Section: Discussionsupporting

confidence: 91%

“…Previous studies have reported that both Pg and E2 alone induce NOSII expression in different cell types in the uterus 29 and that Pg stimulates NOSII expression and NO production in ovarian cancer cells. 30 In contrast, other studies showed an inhibitory effect of Pg. Thus, Pg inhibited NOSII expression in murine macrophages, 31 as well as in human colon enterocytes DLD-1 and Caco-2.…”

Section: Discussionmentioning

confidence: 88%

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Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Bentrari

Arnould́

Jackson

et al. 2005

Laboratory Investigation

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The presence of hormone receptors is related to survival outcome in breast cancer. Previous results from our laboratory established a correlation between the presence of nitric oxide synthase II (NOSII) and nitric oxide (NO) production with progesterone receptors in a series of human breast tumours. Furthermore, this was directly related to a lower tumour grade and a lower proliferation rate of the tumour cells. To examine these results in further detail, the effect of progesterone (Pg) and 17b-oestradiol (E2) on NOSII expression was analysed in the human breast cancer cell line MCF-7. By Northern blot and promoter activity, we show that a cytokine mix (TNF-a, IL-b, and IFN-c) induces NOSII transcription after 6 h stimulation. In the absence of cytokines, neither hormone affects NOSII expression. However, Pg but not E2, enhances cytokine-induced NOSII transcription as well as NO synthesis, mainly by cooperation with gamma-interferon. The increase in NO accumulation in the media induced by addition of Pg to the cytokine treatment significantly increases cell death, mainly accounted for by apoptosis, as compared to the effect of cytokines alone. Our findings help clarify the role of steroid hormones in NOSII expression as well as the effect on cell viability and may suggest novel approaches towards hormonotherapy and the treatment of cancer. Keywords: NOSII; progesterone; transcription; breast cancer; apoptosis; nitric oxide Endogenous nitric oxide (NO) is produced in cells by the nitric oxide synthases (NOS), which exist as three isoforms. The calcium-dependent endothelial (eNOS or NOSIII) and neuronal (nNOS or NOSI) enzymes are constitutively present in various cell types and produce low levels of short acting NO. 1 The third isoform (iNOS or NOSII) is induced in most cell types only in response to external stimuli such as bacterial lipopolysaccharides (LPS) or diverse cytokines, and generates high sustained levels of NO. 2 NO is a transcellular messenger that plays an important role in diverse physiological processes such as vascular homeostasis, immunity and neurotransmission. The effect of endogenous NO on cellular homeostasis is highly dependent on the level of its synthesis. Thus, at low levels it can promote cell proliferation and angiogenesis whereas at high concentrations, such as those produced by NOSII, it can lead to cell damage and death. 3 Therefore, it is important to understand the regulation of the NOS enzymes in order to unravel the role of NO in physiological and pathological conditions. So far it is known that expression of NOSII is regulated mainly at the transcriptional level, although additional post-transcriptional and posttranslational controls have been documented. 4 The most important transcription factors required for NOSII expression are nuclear factor kappa B (NFkB) 5 and activator protein 1 (AP-1). 6 These transcription factors are induced or activated by cytokines such as tumour necrosis alpha (TNF-a), interleukin-1beta (IL-1b), gamma interferon (IFN-g) or LPS. 7 However, differenc...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Bentrari

Arnould́

Jackson

et al. 2005

Laboratory Investigation

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“…Previous studies suggest that SKOV-3 cells are growth-resistant to estradiol [57,58]. It has been suggested that over-expression of HER-2/neu and cathepsin D in SKOV-3 cells interferes with the mitogenic pathways, resulting in unresponsiveness of SKOV-3 cells to estradiol [57].…”

Section: Discussionmentioning

confidence: 98%

Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells

Ramayya

Sheng

Moroz

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…This may in part explain the decrease in PGRMC1 mRNA levels after stimulation of SKOV-3 cells with P4. A P4 concentration of 1000 nM is physiological in the ovary, in which even higher concentrations of P4 are present (37). The smaller effects on the PGRMC1 mRNA levels compared to effects on the let-7i levels (20% for PGRMC1 to 40% for let-7i) can be explained by the fact that let-7i also targets many other mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

Wendler¹

2010

Oncol Rep

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Abstract. PGRMC1 (progesterone receptor membrane component 1) is part of a multi-protein complex, that is highly expressed in several cancers and is involved in chemoresistance. Although PGRMC1 plays an important role in various cancers, little is known about how PGRMC1 expression is regulated. Therefore, the present study was designed to elucidate the molecular mechanisms that influence PGRMC1 expression in ovarian cancer cells. An in silico approach revealed that the 3'-untranslated region of PGRMC1 contains one highly and one poorly conserved binding site for the microRNA let-7/miR-98 and one highly conserved binding site for miR-141/200a. Luciferase assays and real-time PCRs showed that the let-7 isoforms let-7i and miR-98 target PGRMC1 in SKOV-3 cells. In contrast, the conserved binding site for miR-200a/141 in the 3'-UTR of PGRMC1 is not functional. Stimulation of SKOV-3 cells with progesterone resulted in a decrease in PGRMC1 mRNA levels. Further, an analysis of endogenous let-7i levels in SKOV-3 cells revealed that let-7i expression increased after stimulation with progesterone. Therefore, progesterone may exert its effect on PGRMC1 expression in part by stimulation of let-7i. In conclusion, we propose that PGRMC1 expression is regulated by the miRNAs let-7/miR-98, which could become therapeutic targets, as PGRMC1, like many other targets of let-7, seems to be involved in cancer proliferation and chemotherapy resistance.

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Inhibitory Effects of 17β-Estradiol and Progesterone on Ovarian Carcinoma Cell Proliferation: A Potential Role for Inducible Nitric Oxide Synthase

Cited by 42 publications

References 30 publications

Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Human steroidogenic factor-1 (hSF-1) regulates progesterone biosynthesis and growth of ovarian surface epithelial cancer cells

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

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