Inhibitory Effects of Progesterone on Plasma Membrane Fluidity and Tumorigenic Potential of Ovarian Epithelial Cancer Cells

McDonnel, Anna C.; Kirk, Edward A. Van; Isaak, Dale D.; Murdoch, William J.

doi:10.1177/153537020322800310

Cited by 30 publications

(25 citation statements)

References 38 publications

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“…This mechanism is consistent with the in vitro responses. Moreover, the apoptotic action of P4 is observed at 10 nM, which approximates serum levels of P4 (10).…”

Section: Discussionmentioning

confidence: 90%

Progesterone Receptor Membrane Component-1 Regulates the Development and Cisplatin Sensitivity of Human Ovarian Tumors in Athymic Nude Mice

et al. 2009

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To determine whether progesterone receptor membrane component 1 (PGRMC1) regulates the development and cisplatin (CDDP)-sensitivity of human ovarian tumors, PGRMC1 was depleted from a human ovarian cancer cell line, dsRed-SKOV-3 cells, using a short hairpin RNA knockdown approach. Compared with parental dsRed-SKOV-3 cells, the PGRMC1-deplete cells grew slower in vitro and did not show progesterone's (P4) antiapoptotic effect. In fact, P4 induced apoptosis in PGRMC1-deplete cells in a dose-dependent manner. When transplanted into the peritoneum of athymic nude mice, parental dsRed-SKOV-3 cells developed numerous tumors, which were classified as either typical or oxyphilic clear cell tumors. CDDP increased the percentage of apoptotic nuclei in typical clear cell tumors and P4 attenuated CDDP-induced apoptosis. In contrast, the percentage of apoptotic nuclei in oxyphilic clear cell tumors was low (< or =1%) and was not significantly affected by CDDP and/or P4. Compared with tumors derived from parental dsRed SKOV-3 cells, PGRMC1-deplete tumors: 1) developed in fewer mice, 2) formed less frequently, 3) appeared smaller, and 4) resulted in fewer oxyphilic clear cell tumors. These PGRMC1-deplete tumors were not responsive to CDDP's apoptotic effects. The failure to respond to CDDP could be due to their poorly developed microvasculature system as judged by percentage of CD31-stained endothelial cells and/or their increased expression of ATP-binding cassette transporters, which are involved in drug resistance. Taken together, these findings indicate that PGRMC1 plays an essential role in the development and CDDP sensitivity of human ovarian tumors.

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“…This mechanism is consistent with the in vitro responses. Moreover, the apoptotic action of P4 is observed at 10 nM, which approximates serum levels of P4 (10).…”

Section: Discussionmentioning

confidence: 90%

Progesterone Receptor Membrane Component-1 Regulates the Development and Cisplatin Sensitivity of Human Ovarian Tumors in Athymic Nude Mice

et al. 2009

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“…* TGF-h target genes identified by select gene expression profiling studies (47^50). cancer cells (37), lower concentrations increased the proliferative capacity of ovarian surface epithelium and ovarian cancer cells in culture (38). This is consistent with the postulate that luteal-phase levels of progesterone have a growth promotional effect, whereas the higher levels achieved during pregnancy or oral contraceptive use induce cell cycle arrest or apoptosis of epithelial cells (32).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Tone

Begley²,

Sharma

et al. 2008

Clinical Cancer Research

125

111

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Purpose:To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa. Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa. Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription^PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples. Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.

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“…Membrane fluidity was decreased by doses of progesterone ≥0.1 μg/ml [6]. Microplates were seeded with SKOV-3 or OVCAR-3 cells (12,000/well) and incubated for 24 hours with medium only, cisplatin (0.1 μg/ml), progesterone (0.01, 0.1 μg/ml), or cisplatin + progesterone.…”

Section: In Vitro Effects Of Cisplatin And(or) Progesterone On Cellulmentioning

confidence: 99%

“…The experiment was terminated 24 hours following vehicle/cisplatin injections at six weeks post-xenograft. Serum (tail vein) and ip fluid samples were collected for progesterone radioimmunoassay [6]. Tumor parameters were assessed as described for Experiment 3.…”

Section: Antitumor Effects Of Progesterone And(or) Cisplatin (Experimmentioning

confidence: 99%

“…A putative strategy to potentiate drug retention and consequently overcome resistance is to disrupt exporter dynamics by causing membrane rigidification [5]. Progesterone attenuated fluidity of human epithelial ovarian cancer cells [6]. Objectives were to determine if vulnerabilities of cells and xenografts to cisplatin are altered by progesterone.…”

Section: Introductionmentioning

confidence: 99%

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Progesterone facilitates cisplatin toxicity in epithelial ovarian cancer cells and xenografts

Murdoch

Kirk

Isaak

et al. 2008

Gynecologic Oncology

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Objectives-The underlying premise of these investigations was that the lipophilic hormone progesterone, which partitions into and (at relatively high concentrations) impedes the fluid mechanics of the plasmalemma, would perturb integral associations between membrane lipids and exporter pumps that otherwise confer drug resistance. That progesterone can affect susceptibility of ovarian adenocarcinoma cells and xenografts to cisplatin was tested.Methods-The cisplatin-resistant human cell lines SKOV-3 and OVCAR-3 were treated for 24 hours with cisplatin (0.1 μg/ml) ± progesterone (0.01, 0.1 μg/ml). Cytotoxicity and platinum were measured by MTT assay and inductively coupled plasma mass spectrometry, respectively. Athymic mice were inoculated intraperitoneal (ip) with SKOV-3 cells. Cisplatin (2 mg/kg/week) ± progesterone (25 mg sustained-release pellet) regimens were initiated ip at one week (when micrometastases were present) and continued to six weeks post-xenograft. Tumor burdens, histopathology, and platinum concentrations were assessed upon necropsy at 24 hours after the final injection of cisplatin.Results-There were no significant in vitro/vivo anticancer effects of cisplatin alone. High-dose progesterone enhanced platinum accretion and induced drug toxicity in both cell lines. Tumorigenesis was suppressed by cisplatin + progesterone. The treatment synergy was related to elevated tumor platinum and morphological evidence of apoptosis.Conclusion-It appears that the addition of progesterone to ovarian cancer therapeutic modalities represents a step in improving responses.

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Inhibitory Effects of Progesterone on Plasma Membrane Fluidity and Tumorigenic Potential of Ovarian Epithelial Cancer Cells

Cited by 30 publications

References 38 publications

Progesterone Receptor Membrane Component-1 Regulates the Development and Cisplatin Sensitivity of Human Ovarian Tumors in Athymic Nude Mice

Progesterone Receptor Membrane Component-1 Regulates the Development and Cisplatin Sensitivity of Human Ovarian Tumors in Athymic Nude Mice

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Progesterone facilitates cisplatin toxicity in epithelial ovarian cancer cells and xenografts

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