Cyclic AMP in Ovarian Cancer Cells Both Inhibits Proliferation and Increases c-KIT Expression

Shaw, Tanya J.; Keszthelyi, Eniko J.; Tonary, Angela M.; Cada, Michaela; Vanderhyden, Barbara C.

doi:10.1006/excr.2001.5426

Cited by 37 publications

(30 citation statements)

References 39 publications

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“…Neither the PDE4 inhibitors nor 8-bromo-cAMP affected the expression of Kitlg. This is in line with a previous report that cAMP does not stimulate KITLG in GC (Grimaldi et al 2003) but in contrast to findings from ovarian cancer cells (Shaw et al 2002). The lack of effect on Inha expression suggests that PDE4 inhibition alone is not able to generate a sufficient elevation of cAMP to cause a biological effect in the neonatal ovaries as the high dose 8-bromo-cAMP did increase Inha expression.…”

Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 91%

“…It is possible that cAMP interacts with the PI3Kinase pathway through exchange protein directly activated by cAMP (EPAC) in the oocyte as seen in skeletal muscle (Baviera et al 2010). Alternatively, cAMP may increase the production of Kit ligand (KITLG), also known as stem cell factor, in the granulosa cells (GC) as gene expression of KITLG has been shown to be stimulated by cAMP in Sertolli cells, and in ovarian cancer cells (Shaw et al 2002, Grimaldi et al 2003. KITLG can also activate AKT though its receptor cKIT located on the oocyte (De Miguel et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15-26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation. Reproduction (2015) 150 11-20

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Section: Phosphodiesterases In the Rat Ovarysupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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“…The association of KIT with high growth fraction is consistent with presumed proliferation promoting effect of KIT. However, in ovarian carcinoma cell lines, KIT inhibition by anti-KIT neutralising antibodies or the KIT inhibitor STI571 did not alter the growth rate (Shaw et al, 2002). The real biological role of KIT in ovarian carcinoma cells remains to be clarified.…”

Section: Discussionmentioning

confidence: 94%

“…We used the same antibody dilution and IHC protocol as routinely used in GIST diagnostics. Weak expression was found to be mainly cytoplasmic, whereas in strongly positive cases, membranous staining was also detected, presumably representing the active form of KIT protein (Tian et al, 1999;Shaw et al, 2002).…”

Section: Discussionmentioning

confidence: 95%

Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma

et al. 2004

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KIT and PDGFRA are receptor tyrosine kinases that can be specifically inactivated by small-molecule tyrosine kinase inhibitors, notably imatinib mesylate. In ovarian carcinoma, expression of KIT and PDGFRA protein has been documented, but the frequency and the molecular background of expression are poorly known. We analysed the expression of KIT and PDGFRA by immunohistochemistry in 522 serous ovarian carcinomas, and mutations of KIT and PDGFRA by denaturing high-performance liquid chromatographyin 125 and 187 serous ovarian carcinomas, respectively. No mutations of KIT or PDGFRA were detected. KIT expression was detected in 12% of carcinomas: low expression in 10% and high expression in 2% of cases. Using normal serous epithelium as a reference, decreased PDGFRA expression was detected in 12% and increased expression in 13% of carcinomas. Both KIT and PDGFRA expression were associated with high tumour grade, high proliferation index and poor patient outcome. By fluorescence in situ hybridisation, no KIT amplification was found in carcinomas with high KIT expression, but two cases showed a relative gain of chromosome 4. In conclusion, no mutations of KIT or PDGFRA were found, but a subset of serous ovarian carcinoma showed overexpression of the proteins, which was associated with aggressive tumour characteristics.

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“…9,22 Moreover, an increased level of intracellular cAMP inhibited T cell proliferation 10,11 and induced apoptosis in cancer cells. 13,[23][24][25][26][27] The effect on the proliferation of ovarian cancer cells of the agents such as taxanes in augmenting AKAP3 mRNA expression should be investigated. These 2 possibilities are not mutually exclusive and could occur simultaneously.…”

Section: Discussionmentioning

confidence: 99%

A‐kinase anchoring protein 3 messenger RNA expression in ovarian cancer and its implication on prognosis

Hasegawa

Ono

Matsushita

et al. 2003

Intl Journal of Cancer

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A-kinase anchoring protein 3 (AKAP3) is a sperm protein and its expression appears to be restricted to the testis in normal adult tissues. We investigated AKAP3 mRNA expression in 20 normal ovaries and 54 ovarian cancers of different histological types, grades and stages by reverse transcriptionpolymerase chain reaction (RT-PCR). The PCR products were analyzed by conventional agarose gel electrophoresis and capillary electrophoresis on a microtip device to determine the expression semiquantitatively. Little or no expression was observed in the 20 normal ovarian specimens. High AKAP3 mRNA expression was observed in 15 ovarian cancer specimens (28 %). Ovarian cancer represents the fifth leading cause of death from cancers in women, and the first in gynecological malignancies. 1 Because of difficulties in detection, diagnosis and treatment, the overall survival rate of ovarian cancer patients is still poor. 2,3 It is therefore necessary to overcome these difficulties. Since the discovery of human tumor antigens recognized by T-lymphocytes, 4 immunotherapy has received particular attention as one of the new modalities for cancer therapy. 5 Cancer/testis (CT) antigens, which express only in the testis in normal adult tissues and a variety of cancers, would be potential targets for human cancer vaccination. 6 There are now more than 14 genes or gene families coding for CT antigens, 6,7 e.g., MAGE, SSX, NY-ESO-1/LAGE, SCP-1 and OY-TES-1.A-kinase anchoring proteins (AKAPs) are a group of structurally diverse proteins that bind to the regulatory subunit of protein kinase A (PKA). They localize in discrete sites in a cell and enable PKA to be exposed to cAMP efficiently. 8 Recently, it has been demonstrated that AKAP-mediated PKA activation inhibited cell growth in the muscle 9 and T lymphocytes. 10,11 Paclitaxel, docetaxel and vincristine, which were shown to damage microtubules, also activate PKA and induce hyperphosphorylation of Bcl-2, cause growth arrest and apoptosis. 12,13 Chemotherapy using a paclitaxel-based regimen is now commonly used for the treatment of postoperative ovarian cancer patients. 14,15 In our study, we investigated AKAP3 mRNA expression in normal ovary and ovarian cancer, semiquantitatively using capillary electrophoresis on a microtip. A previous study showed that AKAP3 belonged to sperm proteins and the mRNA expression was observed only in the testis in normal adult tissues. 16 We showed that high AKAP3 mRNA expression was observed in ovarian cancer and the expression was correlated to the histological grade and clinical stage of the tumor. The expression in the normal ovary was only marginal. Thus, AKAP3 appeared to be a cancer/testis (CT) antigen. Furthermore, we investigated the relationship between AKAP3 mRNA expression and prognosis. We showed that AKAP3 mRNA expression was an independent and favorable prognostic factor in patients with poorly differentiated ovarian cancer. MATERIAL AND METHODS Patients and specimensFifty-four patients were investigated in our study with a median age of 54 ...

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Cyclic AMP in Ovarian Cancer Cells Both Inhibits Proliferation and Increases c-KIT Expression

Cited by 37 publications

References 39 publications

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma

A‐kinase anchoring protein 3 messenger RNA expression in ovarian cancer and its implication on prognosis

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