Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium
© Choi et al; licensee BioMed Central Ltd. 2003
Received: 11 July 2003
Accepted: 07 October 2003
Published: 07 October 2003
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.
It appears that the majority of ovarian tumors arise from the ovarian surface epithelium (OSE), which is a simple squamous-to-cuboidal mesothelium covering the ovary . As mentioned earlier, the MAPK cascade can be activated via both RTKs and GPCRs, which include the receptors of growth factors, gonadotropins and gonadotropin-releasing hormones (GnRH). In ovarian cancer cells, MAPKs are activated and regulated by cisplatin , paclitaxel , endothelin-1  and GnRH  suggesting that the MAPK signaling pathway plays an important role in the regulation of proliferation, survival and apoptosis in response to these external stimuli in ovarian cancer. In this review, we summarize the activation of the MAPK and its signaling cascade induced by hormones, growth factors and chemotherapeutic agents in normal and (pre)neoplastic OSE cells.
Activation of MAPK by hormonal factors
Activation of MAPK by growth factors and cytokines
Endothelin-1 (ET-1) is a potential autocrine regulatory factor in ovarian cancer. Treatment of OVCA 433 ovarian cancer with ET-1 resulted in a phosphorylation of ERK-2 and mitogenic responses. The epidermal growth factor receptor (EGF-R)/ras-dependent pathway may contribute to the activation of MAPK/ERK-2 and mitogenic signaling induced by ET-1 in these cells, suggesting that ET-1 induced activation of MAPK is mediated in part by signaling pathways that are initiated by transactivation of the EGF-R . As autocrine regulators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been demonstrated to activate MAPK kinase (MEK) and p38 MAPK via AKT pathway in HEY ovarian cancer cells. The kinase activity and S473 phosphorylation of Akt induced by LPA and S1P required both MEK and p38 MAPK, and MEK is likely to be upstream of p38 in these cells, suggesting that the requirement for both MEK and p38 is cell type- and stimulus-specific . In rhesus ovarian surface epithelial cells in culture, treatment with extracellular calcium induced an activation of MAPK in the response to cell proliferation in these normal cells . Human interleukin-8 (IL-8) rapidly activated ERK-1/-2 pathway via stimulation of the CXCR-1/2 receptors . By using inhibitors such as genestein and herbimycin A, tyrosine kinases have been shown to be involved in the IL-8 activation of ERK-1/-2 in SKOV-3 cells, suggesting an important cross-talk between the chemokine and growth factor pathways in the migration and proliferation in ovarian cancer cells .
In addition to ERK1/2, the JNK pathway has been suggested to play a role in the cell proliferation and apoptosis in ovarian cancer. For instance, treatment with tumor necrosis factor (TNF) alpha activated ERK1/2 at 10–20 min, and a maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment . Inhibition of TNF alpha-induced ERK1/2 activity by PD98059 was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. These results indicate that ERK1/2 activity may modulate cellular response to TNF alpha. A balance between ERK1/2 and JNK1 activation may be pivotal in the cellular growth and apoptosis response to TNF alpha .
Activation of MAPK by chemotherapeutic agents
Cisplatin has been widely used as a chemotherapeutic agent to treat ovarian cancers, although its use is somewhat limited because of cisplatin-resistance. The molecular mechanism of cisplatin-induced biological effect in ovarian cancer is not well understood. Cisplatin caused a late and prolonged induction of both ERK1/2 and JNK1 activity in a dose-dependent manner, whereas no significant difference was observed in p38 activity in SKOV-3 cells . These results suggest that ERK and other signal transduction pathways may play a role in response to cisplatin and be important for the development of new strategies to enhance the therapeutic use of platinum drugs. In cisplatin-resistant CaOV-3 and cisplatin-sensitive A2780 ovarian cancer cells, cisplatin induced an activation of both ERK and JNK in distinct time and dose patterns . Cisplatin-induced JNK activation was neither extracellular and intracellular Ca2+-dependent nor protein kinase C-dependent, whereas cisplatin-induced ERK activation was extracellular and intracellular Ca2+-dependent and protein kinase C-dependent . In regard to the regulation of apoptosis by cisplatin, it has been shown that cisplatin activated a robust apoptotic pathway involved in the activation of JNK and p38 MAPK in cisplatin-sensitive ovarian cancer cells, whereas it fails to elicit the response in cisplatin-resistant 2008/C13 cells . In cisplatin-resistant cells, the proteolytic activation of MEKK1 by caspase-3 is deficient, suggesting that inadequate caspase-3 processing and MEKK1 activation may induce a cisplatin-resistant phenotype .
The activation of two MAP kinases, JNK1 and ERK1/2 was compared in the cisplatin-sensitive ovarian carcinoma cell line A2780 and the cisplatin-resistant cell lines CP70 and C200 . Distinct patterns of cisplatin-induced JNK1 and ERK1/2 activation were observed in the cell lines with different levels of cisplatin sensitivity, and inhibition of cisplatin-induced ERK1/2 activation appeared to enhance sensitivity to cisplatin in both cisplatin-sensitive and cisplatin-resistant cell lines. It appears that these MAPK pathways may be important in the cisplatin-resistance in ovarian cancer, which can be used as a potential therapeutic strategy . More recent data indicate that cisplatin differentially induced JNK and p38 pathways, with the cisplatin-sensitive cells showing prolonged (8–12 h) activation and the cisplatin-resistant cells showing only transient (1–3 h) activation of JNK and p38 . In addition, the inhibition of cisplatin-induced JNK and p38 activation blocked cisplatin-induced apoptosis and persistent activation of JNK resulted in an increase in the phosphorylation of c-Jun transcription factor, which stimulated a transcription of an immediate downstream target, a death inducer Fas ligand (FasL) in cisplatin-sensitive cells. Thus, it appears that the JNK-c-Jun-FasL-Fas signaling pathway plays an important role in the regulation of cisplatin-induced apoptosis in ovarian cancer cells, and the duration of JNK activation may be essential in the determination of survival or apoptosis in ovarian cancer cells .
Taxol, a microtubule stabilizer, is a useful therapeutic agent for ovarian cancer treatment. Treatment with taxol resulted in an activation of ERK1/2 and p38 MAPK in human ovarian carcinoma cells with distinct kinetics . The low concentrations of taxol (1–100 nM) activated ERK1/2 within 0.5–6 h, whereas a longer exposure (24 h) at low concentrations abrogated ERK1/2 phosphorylation/activation. Higher concentrations (1–10 μM) of taxol resulted in a sharp inhibition of ERK1/2 activity, whereas same concentrations activated p38 kinase at 2 – 24 h, indicating that the activation of MAPK may be dependent on the dose and exposure time of chemotherapeutic agent . Interestingly, treatment with paclitaxel resulted in a phosphorylation of p70S6K (T421/S424) and this paclitaxel-induced phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca(++), PI3K, and mammalian target of rapamycin (mTOR). Thus, paclitaxel is able to induce p70S6K phosphorylation and exert its antitumor effect via multiple signaling pathways, especially inhibition of p70S6K .
Genes related with the activation of MAPK
The expression levels of kinases have compared in normal, immortalized and neoplastic OSE cells . The expression levels of casein kinase II (CK2), p38 MAPK, cyclin-dependent kinase, and the phosphatidylinositol 3-kinase (PI3K) effectors Akt2 and p70 S6 kinase (S6K) were several-fold higher in neoplastic OSE than in normal OSE, whereas no significant difference was observed in the expression of ERK1/2 . Interestingly, c-Jun NH2-kinase but not PI3-K resulted in telomerase activity. An inhibition of JNK by a specific inhibitor reversed telomerase activity, while the expression of JNK induced an activation of a reporter gene fused to the hTERT promoter sequence at transcriptional level, indicating that JNK plays a critical role in the regulation of telomerase activity and may provide possible therapeutic approaches to ovarian cancer . In addition, the correlation between BRCA1 and stress-associated MAPK has been proposed in ovarian cancer cells . The JNK, an apoptotic signaling pathway, was induced by overexpression of BRCA1, and BRCA1 enhanced the signaling pathways that sequentially involved H-Ras, MEKK4, JNK, Fas ligand/Fas interactions, and caspase-9 activation .
Recently, it has been shown that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and its overexpression may be related with enhanced tumorigenicity. Furthermore, overexpression of gamma-synuclein resulted in a constitutive activation of ERK1/2 and down-regulation of JNK1 in response to environmental stress signals, including UV, arsenate and heat shock . The cross-talk between the MAPK signaling pathway and multi-drug resistant protein MDR-1 has been suggested in terms of sensitivity or resistance to chemotherapy. A constitutive activation of the ERK1/2 pathway was observed, whereas the level of active JNK and p38 remained unchanged in the taxol resistant cells. Inhibition of the ERK1/2 pathway by specific inhibitors, UO126 or PD098059, resulted in a re-sensitization in the taxol resistant cells .
There is some evidence that the MAPK pathway may play a role in the metastasis of ovarian cancer. Treatment of ovarian cancer cells with MEK1 inhibitors, U0126 and PD98059, induced a significant suppression of the MMP-9 secretion activated by fibronectin (FN), suggesting an importance of these signaling molecules as a chemotherapeutic target for cancer to prevent metastasis . The urokinase-type plasminogen activator receptor (u-PAR) has been implicated in tumor progression, and the expression of this gene is strongly up-regulated by phorbol 12-myristate 13-acetate (PMA), a PKC activator. Treatment of the u-PAR-deficient ovarian cancer OVCAR-3 cells, which contain low JNK activities, with PMA resulted in a rapid (5 min) activation of JNK pathway. This finding suggests that the PMA- or c-Ha-Ras-dependent stimulation of u-PAR gene expression requires a JNK1-dependent signaling module .
PCKL is the recipient of a Distinguished Scholar Award from the Michael Smith Foundation for Health Research. This work was supported by the Canadian Institutes of Health Research.
- Davis RJ: MAPKs: new JNK expands the group. Trends Biochem Sci. 1994, 19: 470-473. 10.1016/0968-0004(94)90132-5.View ArticlePubMedGoogle Scholar
- Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002, 1911-1912. 10.1126/science.1072682.Google Scholar
- Cobb MH, Goldsmith EJ: How MAP kinases are regulated. J Biol Chem. 1995, 270: 14843-14846. 10.1074/jbc.270.25.14843.View ArticlePubMedGoogle Scholar
- Fanger GR: Regulation of the MAPK family members: Role of subcellular localization and architectural organization. Histol Histopathol. 1999, 14: 887-894.PubMedGoogle Scholar
- Garrington T, Johnson GL: Organization and regulation of mitogen-activated protein kinase signaling pathway. Curr Opin Cell Biol. 1999, 11: 211-218. 10.1016/S0955-0674(99)80028-3.View ArticlePubMedGoogle Scholar
- Robinson MJ, Cobb MH: Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997, 9: 180-186. 10.1016/S0955-0674(97)80061-0.View ArticlePubMedGoogle Scholar
- Wasylyk B, Hagman J, Gutierrez-Hartmann A: Ets transcription factors: nuclear effectors of the Ras-MAP kinase signaling pathway. Trends Biol Sci. 1998, 23: 213-216. 10.1016/S0968-0004(98)01211-0.View ArticleGoogle Scholar
- Auersperg N, Maines-Bandiera SL, Kruk PA: Human ovarian surface epithelium: growth patterns and differentiation. In: Ovarian Cancer 3. Edited by: Sharp F, Mason P, Blacket T, Berek J. 1995, Champman & Hall, London, 157-169.Google Scholar
- Persons DL, Yazlovitskaya EM, Cui W, Pelling JC: Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. Clin Cancer Res. 1999, 5: 1007-1014.PubMedGoogle Scholar
- Wang TH, Popp DM, Wang HS, Saitoh M, Mural JG, Henley DC, Ichijo H, Wimalasena J: Microtubule dysfunction induced by paclitaxel initiates apoptosis through both c-Jun N-terminal kinase (JNK)-dependent and -independent pathways in ovarian cancer cells. J Biol Chem. 1999, 274: 8208-8216. 10.1074/jbc.274.12.8208.View ArticlePubMedGoogle Scholar
- Vecca F, Bagnato A, Catt KJ, Tecce R: Transactivation of the epidermal growth factor receptor in endothelin-1 induced mitogenic signaling in human ovarian carcinoma cells. Cancer Res. 2000, 60: 5310-5317.Google Scholar
- Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, Kanda Y, Nishio Y, Jikihara H, Matsuura N, Murata Y: Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line. Cancer Res. 1999, 59: 5133-5142.PubMedGoogle Scholar
- Kang SK, Tai CJ, Cheng KW, Leung PC: Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells. Mol Cell Endocrinol. 2000, 170: 143-151. 10.1016/S0303-7207(00)00320-8.View ArticlePubMedGoogle Scholar
- Chamson-Reig A, Sorianello EM, Catalano PN, Fernandez MA, Pignataro OP, Libertun C, Lux-Lantos VA: Gonadotropin-releasing hormone signaling pathways in an experimental ovarian tumor. Endocrinology. 2003, 144: 2957-2966. 10.1210/en.2003-0011.View ArticlePubMedGoogle Scholar
- Zheng W, Magid MS, Kramer EE, Chen YT: Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube. Am J Pathol. 1996, 148: 47-53.PubMed CentralPubMedGoogle Scholar
- Zheng W, Lu JJ, Luo F, Zheng Y, Feng YJ, Felix JC, Lauchlan SC, Pike MC: Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone. Gynecol Oncol. 2000, 76: 80-88. 10.1006/gyno.1999.5628.View ArticlePubMedGoogle Scholar
- Wimalasena J, Dostal R, Meehan D: Gonadotropins, estradiol, and growth factors regulate epithelial ovarian cancer cell growth. Gynecol Oncol. 1992, 46: 345-350.View ArticlePubMedGoogle Scholar
- 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. J Clin Endocrinol Metab. 2002, 87: 2245-2253. 10.1210/jc.87.5.2245.View ArticlePubMedGoogle Scholar
- Batra S, Fadeel I: Release of intracellular calcium and stimulation of cell growth by ATP and histamine in human ovarian cancer cells (SKOV-3). Can Lett. 1994, 77: 57-63.View ArticleGoogle Scholar
- Schultze-Mosgau A, Katzur A, Arora KK, Stojilkovic SS, Diedrich K, Ortmann O: Characterization of calcium-mobilizing P2Y2 receptors in human ovarian cancer cells. Mol Hum Reprod. 2000, 6: 435-442. 10.1093/molehr/6.5.435.View ArticlePubMedGoogle Scholar
- Choi K-C, Tai C-J, Tzeng C-R, Auersperg N, Leung PCK: Adenosine triphosphate (ATP) activates mitogen-activated protein kinases (MAPKs) in neoplastic ovarian surface epithelium (OSE) cells. Biol Reprod. 2003, 68: 309-315.View ArticlePubMedGoogle Scholar
- Baudhuin LM, Cristina KL, Lu J, Xu Y: Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific. Mol Pharmacol. 2002, 62: 660-671. 10.1124/mol.62.3.660.View ArticlePubMedGoogle Scholar
- Wright JW, Toth-Fejel S, Stouffer RL, Rodland KD: Proliferation of rhesus ovarian surface epithelial cells in culture: lack of mitogenic response to steroid or gonadotropic hormones. Endocrinology. 2002, 143: 2198-2207. 10.1210/en.143.6.2198.View ArticlePubMedGoogle Scholar
- Venkatakrishnan G, Salgia R, Groopman JE: Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. J Biol Chem. 2000, 275: 6868-6875. 10.1074/jbc.275.10.6868.View ArticlePubMedGoogle Scholar
- Yazlovitskaya EM, Pelling JC, Persons DL: Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101. Mol Carcinog. 1999, 25: 14-20. 10.1002/(SICI)1098-2744(199905)25:1<14::AID-MC2>3.3.CO;2-M.View ArticlePubMedGoogle Scholar
- Hayakawa J, Ohmichi M, Kurachi H, Ikegami H, Kimura A, Matsuoka T, Jikihara H, Mercola D, Murata Y: Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J Biol Chem. 1999, 274: 31648-31654. 10.1074/jbc.274.44.31648.View ArticlePubMedGoogle Scholar
- Gebauer G, Mirakhur B, Nguyen Q, Shore SK, Simpkins H, Dhanasekaran N: Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian adenocarcinoma 2008/C13 cells. Int J Oncol. 2000, 16: 321-325.PubMedGoogle Scholar
- Cui W, Yazlovitskaya EM, Mayo MS, Pelling JC, Persons DL: Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal-regulated protein kinases 1 and 2 in a series of cisplatin-resistant ovarian carcinoma cell lines. Mol Carcinog. 2000, 29: 219-228. 10.1002/1098-2744(200012)29:4<219::AID-MC1004>3.3.CO;2-4.View ArticlePubMedGoogle Scholar
- Mansouri A, Ridgway LD, Korapati AL, Zhang Q, Tian L, Wang Y, Siddik ZH, Mills GB, Claret FX: Sustained activation of JNK-p38 MAP kinase pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. J Biol Chem. 2003Google Scholar
- Seidman R, Gitelman I, Sagi O, Horwitz SB, Wolfson M: The role of ERK 1/2 and p38 MAP-kinase pathways in taxol-induced apoptosis in human ovarian carcinoma cells. Exp Cell Res. 2001, 268: 84-92. 10.1006/excr.2001.5262.View ArticlePubMedGoogle Scholar
- Le XF, Hittelman WN, Liu J, McWatters A, Li C, Mills GB, Bast RC: Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis. Oncogene. 2003, 22: 484-497. 10.1038/sj.onc.1206175.View ArticlePubMedGoogle Scholar
- Wong AS, Kim SO, Leung PC, Auersperg N, Pelech SL: Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Gynecol Oncol. 2001, 82: 305-311. 10.1006/gyno.2001.6280.View ArticlePubMedGoogle Scholar
- Alfonso-De Matte MY, Yang H, Evans MS, Cheng JQ, Kruk PA: Telomerase is regulated by c-Jun NH2-terminal kinase in ovarian surface epithelial cells. Cancer Res. 2002, 62: 4575-4578.PubMedGoogle Scholar
- Thangaraju M, Kaufmann SH, Couch FJ: BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. J Biol Chem. 2000, 275: 33487-33496. 10.1074/jbc.M005824200.View ArticlePubMedGoogle Scholar
- Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK: Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J Biol Chem. 2002, 277: 35050-35060. 10.1074/jbc.M201650200.View ArticlePubMedGoogle Scholar
- Ding S, Chamberlain M, McLaren A, Goh L, Duncan I, Wolf CR: Cross-talk between signalling pathways and the multidrug resistant protein MDR-1. Br J Cancer. 2001, 85: 1175-1184. 10.1054/bjoc.2001.2044.PubMed CentralView ArticlePubMedGoogle Scholar
- Thant AA, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein TT, Amin AR, Hamaguchi M: Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin Exp Metastasis. 2000, 18: 423-428. 10.1023/A:1010921730952.View ArticlePubMedGoogle Scholar
- Gum R, Juarez J, Allgayer H, Mazar A, Wang Y, Boyd D: Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules. Oncogene. 1998, 17: 213-225. 10.1038/sj.onc.1201917.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.