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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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The effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian cancer line. The phosphorylated form (P-MAPK) normalized by total form (T-MAPK) was analyzed in a dose-dependent manner by immunoblot analysis in OVCAR-3 cells treated with GnRH. Values are represented as the mean ± SD of three individual experiments. a, P < 0.05 versus untreated control. [Reproduced, permission with, from: Kang SK, Tai CJ, Cheng KW, Leung PC; "Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells" in: Mol Cell Endocrinol 2000, 170:143–151. Copyright from Elsevier]
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Figure 2: The effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian cancer line. The phosphorylated form (P-MAPK) normalized by total form (T-MAPK) was analyzed in a dose-dependent manner by immunoblot analysis in OVCAR-3 cells treated with GnRH. Values are represented as the mean ± SD of three individual experiments. a, P < 0.05 versus untreated control. [Reproduced, permission with, from: Kang SK, Tai CJ, Cheng KW, Leung PC; "Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells" in: Mol Cell Endocrinol 2000, 170:143–151. Copyright from Elsevier]

Mentions: There is increasing evidence that gonadotropin-releasing hormone (GnRH) and its agonists (GnRHa) may play a critical role in the inhibition of cell proliferation in gynecological cancers including ovarian and endometrial cancers. However, their biological mechanism remains to be uncovered. The GnRH receptor (GnRH-R) belongs to the family of GPCRs. MAPK has been implicated in the antiproliferative effect of GnRHa in CaOV-3 ovarian cancer cell line [12]. Treatment of CaOV-3 cells with GnRHa resulted in an activation of ERK at 5 min, reached the highest activation at 3 h and sustained until 24 h, whereas GnRHa had no effect on the activation of the JNK. In addition, the ERK kinase was also activated and an increase in phosphorylation of son of sevenless (Sos), and Shc was observed following GnRHa treatment. Treatment with an inhibitor of mitogen-activated protein/ERK kinase, PD98059 reversed the antiproliferative effect of GnRHa and the GnRH-induced dephosphorylation of the retinoblastoma protein. These results indicate that an activation of ERK may play a role in the antiproliferative effect of GnRHa [12]. In our laboratory, we have shown that an agonist of GnRH (D-Ala6)-GnRH, induced a biphasic pattern of ERK-1/-2 activation in OVCAR-3 cells (Fig. 2). A low concentration of GnRHa (10-10 M) resulted in a significant decrease of MAPK activity, whereas high concentrations (10-7 and 10-6 M) induced an activation of MAPK pathway in ovarian and placental cells [13]. It is of interest to note that GnRH signaling appears to involve ERK-1/-2 phosphorylation through the activation of adenylyl cyclase and PKC in rat luteinized ovarian tumors [14].


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

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

The effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian cancer line. The phosphorylated form (P-MAPK) normalized by total form (T-MAPK) was analyzed in a dose-dependent manner by immunoblot analysis in OVCAR-3 cells treated with GnRH. Values are represented as the mean ± SD of three individual experiments. a, P < 0.05 versus untreated control. [Reproduced, permission with, from: Kang SK, Tai CJ, Cheng KW, Leung PC; "Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells" in: Mol Cell Endocrinol 2000, 170:143–151. Copyright from Elsevier]
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC239898&req=5

Figure 2: The effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian cancer line. The phosphorylated form (P-MAPK) normalized by total form (T-MAPK) was analyzed in a dose-dependent manner by immunoblot analysis in OVCAR-3 cells treated with GnRH. Values are represented as the mean ± SD of three individual experiments. a, P < 0.05 versus untreated control. [Reproduced, permission with, from: Kang SK, Tai CJ, Cheng KW, Leung PC; "Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells" in: Mol Cell Endocrinol 2000, 170:143–151. Copyright from Elsevier]
Mentions: There is increasing evidence that gonadotropin-releasing hormone (GnRH) and its agonists (GnRHa) may play a critical role in the inhibition of cell proliferation in gynecological cancers including ovarian and endometrial cancers. However, their biological mechanism remains to be uncovered. The GnRH receptor (GnRH-R) belongs to the family of GPCRs. MAPK has been implicated in the antiproliferative effect of GnRHa in CaOV-3 ovarian cancer cell line [12]. Treatment of CaOV-3 cells with GnRHa resulted in an activation of ERK at 5 min, reached the highest activation at 3 h and sustained until 24 h, whereas GnRHa had no effect on the activation of the JNK. In addition, the ERK kinase was also activated and an increase in phosphorylation of son of sevenless (Sos), and Shc was observed following GnRHa treatment. Treatment with an inhibitor of mitogen-activated protein/ERK kinase, PD98059 reversed the antiproliferative effect of GnRHa and the GnRH-induced dephosphorylation of the retinoblastoma protein. These results indicate that an activation of ERK may play a role in the antiproliferative effect of GnRHa [12]. In our laboratory, we have shown that an agonist of GnRH (D-Ala6)-GnRH, induced a biphasic pattern of ERK-1/-2 activation in OVCAR-3 cells (Fig. 2). A low concentration of GnRHa (10-10 M) resulted in a significant decrease of MAPK activity, whereas high concentrations (10-7 and 10-6 M) induced an activation of MAPK pathway in ovarian and placental cells [13]. It is of interest to note that GnRH signaling appears to involve ERK-1/-2 phosphorylation through the activation of adenylyl cyclase and PKC in rat luteinized ovarian tumors [14].

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