Mechanisms of Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Itamochi, Hiroaki; Kigawa, Junzo; Akeshima, Ryoji; Sato, Shinya; Kamazawa, Shunji; Takahashi, Masakuni; Kanamori, Yasunobu; Suzuki, Mitsuaki; Ohwada, Michitaka; Terakawa, Naoki

doi:10.1159/000065067

Cited by 50 publications

(49 citation statements)

References 18 publications

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“…Conversely, given the mitogenic effect of cyclin E and the increase in the proportion of cells in S phase in cyclin E overexpressing cells, drugs that cause DNA damage may have greater efficacy. In ovarian carcinoma, the response to cisplatin therapy has been linked to the proliferative rate of the tumor (Kolfschoten et al, 2000;Itamochi et al, 2002); tumor cells with high S phase have increased sensitivity to cisplatin treatment (Kolfschoten et al, 2000;Itamochi et al, 2002). Additionally in vitro pharmacologic studies have demonstrated that cyclin E overexpression enhances the cytotoxicity of cisplatin/taxol combination therapy in a panel of different solid tumor cell lines (Smith and Seo, 2000) and that abrogation of the G1/S checkpoint may be involved in increasing the efficacy of cisplatin in ovarian cancer cells (Pestell et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Cyclin E deregulation alters the biologic properties of ovarian cancer cells

Bedrosian

Verschraegen

et al. 2004

Oncogene

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We have previously shown that the low molecular weight (LMW) forms (trunk 1 and trunk 2) of cyclin E are biochemically hyperactive and induce G1/S progression in normal epithelial cells. Here we investigate the biologic consequences of LMW cyclin E expression in ovarian cancer cells. Using a panel of ovarian carcinoma tumors we find that cyclin E overexpression is invariably due to the presence of LMW forms and that expression of these forms appears to correlate with more advanced grade and stage of disease. Despite similar expression of p21 and p27, cyclin E overexpressing tumors have higher kinase function. Using an isogenic ovarian cancer model, we find that clones that overexpress the trunk 1 (T1) protein have a 10-fold increase in cyclin E kinase function, a 20% increase in S-phase fraction, a 10-15% decrease in doubling time and a 20% increase in colony formation compared to parental cells that express only the FL cyclin E protein. T1 clones were resistant to G1 arrest but more sensitive to cisplatin. Therefore, in ovarian tumors, the presence of LMW cyclin E forms confers altered biologic properties. Our data provides a potential mechanism for the poor prognosis of patients with LMW cyclin E expressing tumors.

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Section: Discussionmentioning

confidence: 99%

“…Cisplatin was chosen for these studies as this is commonly used in the treatment of ovarian cancer and ovarian tumor response to cisplatin has been correlated with proliferative rate (Itamochi et al, 2002). We sought to directly test this hypothesis in our isogenic model (Figure 6).…”

Section: Mdah-2774 T1 Clones Are More Sensitive To Cisplatin Cytotoximentioning

confidence: 99%

Cyclin E deregulation alters the biologic properties of ovarian cancer cells

Bedrosian

Verschraegen

et al. 2004

Oncogene

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“…However, clear cell adenocarcinoma has a poorer prognosis than serous carcinoma (2), and the response rate to platinum-based chemotherapy in patients with clear cell adenocarcinoma is significantly lower than that in patients with serous adenocarcinoma (1). The doubling time for clear cell adenocarcinoma cells is significantly longer than that for serous adenocarcinoma cells (3). Clinically, several characteristics distinguish clear cell adenocarcinoma from the other histological types of epithelial ovarian carcinoma, including high frequency of associated endometriosis, resistance to chemotherapy and poor prognosis even in early stage of disease.…”

Section: Introductionmentioning

confidence: 98%

The autocrine effect of activin A on human ovarian clear cell adenocarcinoma cells

Mabuchi¹,

Yamoto²,

Minami³

et al. 2006

Oncol Rep

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Abstract. The functions of activin, a member of TGF-ß superfamily, in ovarian clear cell adenocarcinoma remain unsolved, although we recently found that inhibin ßA-subunit, activin A, activin receptor type IA, type IB, type IIA, type IIB, Smad2, Smad3 and Smad4 were localized in tumor cells of the ovarian clear cell adenocarcinoma tissue by immunohistochemistry. In the present study, in order to investigate the role of activin concerning cell growth in ovarian clear cell adenocarcinoma cells, we determined the production of activin A and inhibin A, and the expression of activin receptors and Smads using the human ovarian clear cell adenocarcinoma cell line JHOC-5. Moreover, we examined the effects of activin A on the activation of activin signaling pathway and on the proliferation in JHOC-5 cells. We detected a measurable amount of activin A in the culture medium of JHOC-5 cells, although inhibin A was not detected. The expression of activin receptor type IA, IB, IIA, IIB, Smad2, Smad3 and Smad4 was observed in JHOC-5 cells. Activin A induced a significant increase in proliferation of JHOC-5 cells compared with the untreated control. On the other hand, activin A did not affect the growth of JHOC-5 cells and no statistically significant difference was observed in the presence of follistatin which is a specific binding protein of activin. Phosphorylated Smad2, an activated form of Smad2, was detected both in treated JHOC-5 cells and in untreated cells by activin A. Activin A significantly increased the expression of phosphorylated Smad2 in JHOC-5 cells. Therefore, it is possible that activin has autocrine roles in tumor growth of ovarian clear cell adenocarcinoma cells.

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“…The incidence of clear-cell tumours among epithelial ovarian cancers is around 10%. Clear-cell tumours tend to be resistant to platinumbased chemotherapy, giving rise to a poor prognosis (Itamochi et al, 2002).…”

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confidence: 99%

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

et al. 2007

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The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-a) making analysis with commercial antibodies difficult. We wanted to establish the expression pattern of eEF1A2 in ovarian cancer of defined histological subtypes at both the RNA and protein level, and to establish the mechanism for the overexpression of eEF1A2 in tumours. We show that while overexpression of eEF1A2 is seen at both the RNA and protein level in up to 75% of clear cell carcinomas, it occurs at a lower frequency in other histological subtypes. The copy number at the EEF1A2 locus does not correlate with expression level of the gene, no functional mutations were found, and the gene is unmethylated in both normal and tumour DNA, showing that overexpression is not dependent on genetic or epigenetic modifications at the EEF1A2 locus. We suggest that the cause of overexpression of eEF1A2 may be the inappropriate expression of a trans-acting factor. The oncogenicity of eEF1A2 may be related either to its role in protein synthesis or to potential non-canonical functions.

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Mechanisms of Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Cited by 50 publications

References 18 publications

Cyclin E deregulation alters the biologic properties of ovarian cancer cells

Cyclin E deregulation alters the biologic properties of ovarian cancer cells

The autocrine effect of activin A on human ovarian clear cell adenocarcinoma cells

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

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