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Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium.

Choi KC, Auersperg N, Leung PC - Reprod. Biol. Endocrinol. (2003)

Bottom Line: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus.It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells.Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynaecology, BC Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5. kchoi@cw.bc.ca

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells. Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer. In this article, an activation of the MAPK signaling cascade by several key reproductive hormones and growth factors in epithelial ovarian cancer is reviewed.

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Effect of FSH in the presence or absence of PD98059 on ERK-1/-2 (p44/p42) activation. The P-MAPK normalized by T-MAPK was analyzed in a dose-dependent manner by immunoblot analysis in IOSE-29 cells treated with FSH. Data are shown as the means of three individual experiments, and are presented as the mean ± SD. a, P < 0.05 vs. untreated control; b, P < 0.05  vs. FSH (100 ng/ml) treatment; c, P < 0.05 vs. PD98059 (50 μM) treatment. 1, untreated control; 2, FSH (10 ng/ml) treatment; 3, FSH (100 ng/ml) treatment; 4, FSH (1000 ng/ml) treatment; 5, FSH (100 ng/ml) treatment; 6, FSH (100 ng/ml) plus PD98059 (50 μM) treatment; 7, PD98059 (50 μM) treatment. [Reproduced, permission with, from: Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC; "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells" in: J Clin Endocrinol Metab 2002, 87:2245–2253. Copyright from Endocrine Society]
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Figure 3: Effect of FSH in the presence or absence of PD98059 on ERK-1/-2 (p44/p42) activation. The P-MAPK normalized by T-MAPK was analyzed in a dose-dependent manner by immunoblot analysis in IOSE-29 cells treated with FSH. Data are shown as the means of three individual experiments, and are presented as the mean ± SD. a, P < 0.05 vs. untreated control; b, P < 0.05 vs. FSH (100 ng/ml) treatment; c, P < 0.05 vs. PD98059 (50 μM) treatment. 1, untreated control; 2, FSH (10 ng/ml) treatment; 3, FSH (100 ng/ml) treatment; 4, FSH (1000 ng/ml) treatment; 5, FSH (100 ng/ml) treatment; 6, FSH (100 ng/ml) plus PD98059 (50 μM) treatment; 7, PD98059 (50 μM) treatment. [Reproduced, permission with, from: Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC; "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells" in: J Clin Endocrinol Metab 2002, 87:2245–2253. Copyright from Endocrine Society]

Mentions: An involvement of gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), has been proposed in the progression and metastasis of ovarian cancer. Expression of FSH receptor (FSH-R), a member of the GPCRs family, has been demonstrated in normal OSE [15], ovarian inclusions and epithelial tumors [16], implicating a potential role of FSH in these cells. Treatment with FSH resulted in a growth-stimulation in ovarian cancer cells in a dose- and time-dependent manner in vitro [16,17]. Despite these findings, the precise molecular mechanism of FSH in terms of growth stimulation and intracellular signaling in ovarian cancer remained unknown. In a recent study, we have investigated the involvement of MAPKs in the mechanism of the growth-stimulatory effect of FSH in pre-neoplastic OSE cells [18]. Treatment with FSH (10, 100 and 1,000 ng/ml) resulted in the MAPK activation of immortalized OSE (IOSE-29) cells as shown in Fig. 3. The stimulatory effect of FSH in the cellular proliferation and MAPK activation was completely abolished in the presence of PD98059, a MEK inhibitor (Fig. 3). In IOSE-29 cells, treatment with FSH significantly increased MAPK activity at 5–10 min, and an activated MAPK declined to control level after 20 min in these cells (Fig. 4). In addition, treatment with FSH resulted in substantial phosphorylation of Elk-1, the Ets family transcriptional factor [18]. These results support the hypothesis that the MAPK cascade is involved in cellular function such as growth stimulation in response to FSH in pre-neoplastic OSE cells.


Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium.

Choi KC, Auersperg N, Leung PC - Reprod. Biol. Endocrinol. (2003)

Effect of FSH in the presence or absence of PD98059 on ERK-1/-2 (p44/p42) activation. The P-MAPK normalized by T-MAPK was analyzed in a dose-dependent manner by immunoblot analysis in IOSE-29 cells treated with FSH. Data are shown as the means of three individual experiments, and are presented as the mean ± SD. a, P < 0.05 vs. untreated control; b, P < 0.05  vs. FSH (100 ng/ml) treatment; c, P < 0.05 vs. PD98059 (50 μM) treatment. 1, untreated control; 2, FSH (10 ng/ml) treatment; 3, FSH (100 ng/ml) treatment; 4, FSH (1000 ng/ml) treatment; 5, FSH (100 ng/ml) treatment; 6, FSH (100 ng/ml) plus PD98059 (50 μM) treatment; 7, PD98059 (50 μM) treatment. [Reproduced, permission with, from: Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC; "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells" in: J Clin Endocrinol Metab 2002, 87:2245–2253. Copyright from Endocrine Society]
© Copyright Policy
Related In: Results  -  Collection

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Figure 3: Effect of FSH in the presence or absence of PD98059 on ERK-1/-2 (p44/p42) activation. The P-MAPK normalized by T-MAPK was analyzed in a dose-dependent manner by immunoblot analysis in IOSE-29 cells treated with FSH. Data are shown as the means of three individual experiments, and are presented as the mean ± SD. a, P < 0.05 vs. untreated control; b, P < 0.05 vs. FSH (100 ng/ml) treatment; c, P < 0.05 vs. PD98059 (50 μM) treatment. 1, untreated control; 2, FSH (10 ng/ml) treatment; 3, FSH (100 ng/ml) treatment; 4, FSH (1000 ng/ml) treatment; 5, FSH (100 ng/ml) treatment; 6, FSH (100 ng/ml) plus PD98059 (50 μM) treatment; 7, PD98059 (50 μM) treatment. [Reproduced, permission with, from: Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC; "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells" in: J Clin Endocrinol Metab 2002, 87:2245–2253. Copyright from Endocrine Society]
Mentions: An involvement of gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), has been proposed in the progression and metastasis of ovarian cancer. Expression of FSH receptor (FSH-R), a member of the GPCRs family, has been demonstrated in normal OSE [15], ovarian inclusions and epithelial tumors [16], implicating a potential role of FSH in these cells. Treatment with FSH resulted in a growth-stimulation in ovarian cancer cells in a dose- and time-dependent manner in vitro [16,17]. Despite these findings, the precise molecular mechanism of FSH in terms of growth stimulation and intracellular signaling in ovarian cancer remained unknown. In a recent study, we have investigated the involvement of MAPKs in the mechanism of the growth-stimulatory effect of FSH in pre-neoplastic OSE cells [18]. Treatment with FSH (10, 100 and 1,000 ng/ml) resulted in the MAPK activation of immortalized OSE (IOSE-29) cells as shown in Fig. 3. The stimulatory effect of FSH in the cellular proliferation and MAPK activation was completely abolished in the presence of PD98059, a MEK inhibitor (Fig. 3). In IOSE-29 cells, treatment with FSH significantly increased MAPK activity at 5–10 min, and an activated MAPK declined to control level after 20 min in these cells (Fig. 4). In addition, treatment with FSH resulted in substantial phosphorylation of Elk-1, the Ets family transcriptional factor [18]. These results support the hypothesis that the MAPK cascade is involved in cellular function such as growth stimulation in response to FSH in pre-neoplastic OSE cells.

Bottom Line: Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus.It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells.Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynaecology, BC Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5. kchoi@cw.bc.ca

ABSTRACT
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. It has been demonstrated that MAPKs are activated by external stimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovarian surface epithelial cells. Thus, the MAPK signaling pathway may play an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer. In this article, an activation of the MAPK signaling cascade by several key reproductive hormones and growth factors in epithelial ovarian cancer is reviewed.

Show MeSH
Related in: MedlinePlus