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J Turk Ger Gynecol Assoc. 2019 Nov 28;20(4):247-254. doi: 10.4274/jtgga.galenos.2018.2018.0140. Epub 2018 Dec 28.

The mammalian target of rapamycin protein expression in human granulosa cell tumors

Author information

1
Department of Obstetrics and Gynecology, Carl von Ossietszky Oldenburg University, Klinikum AöR, Oldenburg, Germany
2
Department of Obstetrics and Gynecology, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey
3
Koç University Graduate School of Health Sciences and School of Medicine, İstanbul, Turkey
4
Department of Pathology, Acıbadem University Faculty of Medicine, İstanbul, Turkey

Abstract

Objective:

To investigate the role of mammalian target of rapamycin (mTOR) in human granulosa cell ovarian tumors and the therapeutic effect of rapamycin in COV434 mitotic granulosa cell lines.

Material and Methods:

A retrospective evaluation of the medical records and pathologic sections of patients with granulosa cell ovarian carcinoma was performed. mTOR and p-mTOR expression was immunohistochemically investigated. A COV434 cell culture were treated with 0.5, 1, 2, and 5 μM rapamycin. Real-time growth curve analysis via xCELLigence system and apoptotic cell analysis via YO-PRO™-1 Iodide were performed to assess the therapeutic effect of rapamycin on cancer cells.

Results:

A total of twenty patients were evaluated. mTOR staining was detected in 18 (90%) patients. Mild, moderate, intense, and very intense staining was observed in three (15%), eight (40%), six (30%), and one (5%) sample, respectively. The mean mTOR staining ratio was 59±41%. P-mTOR staining was observed in two (10%) patients. One (5%) patient had 5% staining, and one (5%) patient had 100% staining for p-mTOR. Both of the latter patients had very intense staining. Rapamycin caused a dose-dependent growth arrest and induced apoptosis in COV434 mitotic granulosa cells. The real-time growth curves of the cells treated with these drugs were distinguished by a marked reduced slope after exposure for several hours, indicating a rapid onset of apoptosis. Live/dead cell analysis with YO-PRO-1 staining showed that rapamycin induced apoptosis in 24% of the cells when used at 1 μM concentration, whereas the rate increased to 61% and 72% when the cells were treated with 2 μM and 5 μM rapamycin, respectively.

Conclusion:

mTOR expression is observed in various degrees in 90%, and p-mTOR expression is observed in only 10% of patients with granulosa cell ovarian carcinoma. Rapamycin caused a dose-dependent growth arrest and apoptosis in COV434 mitotic granulosa cells.

KEYWORDS:

Granulosa cell ovarian tumor; mTOR; rapamycin; ovarian cancer

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