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Mitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epithelium Choi, Kyung-Chul; Auersperg, Nelly; Leung, Peter C Oct 7, 2003

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ralReproductive Biology and ssBioMed CentEndocrinologyOpen AcceReviewMitogen-activated protein kinases in normal and (pre)neoplastic ovarian surface epitheliumKyung-Chul Choi, Nelly Auersperg and Peter CK Leung*Address: Department of Obstetrics and Gynaecology, BC Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5Email: Kyung-Chul Choi - kchoi@cw.bc.ca; Nelly Auersperg - auersper@interchange.ubc.ca; Peter CK Leung* - peleung@interchange.ubc.ca* Corresponding author    MAPKsignaling pathwayovarian cancerAbstractMitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which areactivated in response to a diverse array of extracellular stimuli and mediate signal transduction fromthe cell surface to the nucleus. It has been demonstrated that MAPKs are activated by externalstimuli including chemotherapeutic agents, growth factors and reproductive hormones in ovariansurface epithelial cells. Thus, the MAPK signaling pathway may play an important role in theregulation of proliferation, survival and apoptosis in response to these external stimuli in ovariancancer. In this article, an activation of the MAPK signaling cascade by several key reproductivehormones and growth factors in epithelial ovarian cancer is reviewed.IntroductionMitogen-activated protein kinases (MAPKs) are a group ofserine/threonine kinases which are activated in responseto a diverse array of extracellular stimuli, and mediate sig-nal transduction from the cell surface to the nucleus [1].As illustrated in Fig. 1, three MAPK family including extra-cellular signal-regulated kinases (ERK1 and ERK2), c-junterminal kinase/stress-activated protein kinases (JNK/SAPK) and p38, have been well characterized [2–4]. Inaddition, other MAPK family members, including ERK3, 4and 5, four p38-like kinases and p57 MAPK have beencloned, but the biological role of these MAPKs is not wellunderstood [2,4]. The MAPK cascade is activated via twodistinct classes of cell surface receptors, receptor tyrosinekinases (RTKs) and G protein-coupled receptors (GPCRs).The signals transmitted through this cascade can cause anand ERK2 (p42 MAPK) activated by mitogenic stimuli area group of the most extensively studied members, whereasJNK/SAPK and p38 are activated in response to stress suchas heat shock, osmotic shock, cytokines, protein synthesisinhibitors, antioxidants, ultra-violet, and DNA-damagingagents [5,6]. MAPK family members are directly regulatedby the kinases known as MAPK kinases (MAPKKs), whichactivate the MAPKs by phosphorylation of tyrosine andthreonine residues [2,4,6]. At least seven different MAP-KKs have been cloned and characterized [2,4]. The firstMAPKKs cloned were MAPK/ERK kinase 1 and 2 (MEK 1/2), which specifically activate ERKs. MKK3 and 6 specifi-cally activate p38, whereas MKK5 stimulates the phospho-rylation of ERK5. The MKK4 and 7 are known to activateJNK. The MAPKKs are activated by a rapidly expandinggroup of kinases called MAPKK kinases (MAPKKKs),Published: 07 October 2003Reproductive Biology and Endocrinology 2003, 1:71Received: 11 July 2003Accepted: 07 October 2003This article is available from: http://www.RBEj.com/content/1/1/71© 2003 Choi et al; licensee 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.Page 1 of 8(page number not for citation purposes)activation of diverse molecules which regulate cellgrowth, survival and differentiation. ERK1 (p44 MAPK)which activate the MAPKKs by phosphorylation of serineand threonine residues [4,6]. These include Raf-1, A-Raf,Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71The MAPK signaling transduction pathwaysFigure 1Stress/cytokine Hormones, Growth factors,NeurotransmittersCell proliferation, differentiationand survivalERK1/2Elk-1, c-MycJNK/SAPKElk-1, Jun, ATF2p38Elk-1, AFT2Stress responseTranscriptionalfactorsMAPKG-protein-coupledreceptorsHeat shock, Osmotic shock,UVTNFalpha,IL1a,bTyrosinekinaserecetporsPLCPKC?MAPKKK/ MEKKMEKK RafsMAPKK 3/6 MAPKK/ MEKMAPKK 4/7 MEK1/2Page 2 of 8(page number not for citation purposes)The MAPK signaling transduction pathways.Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71B-raf, MAPK/ERK kinase 1–4 (MEKK1-4), apoptosis-stim-ulating kinase-1 (ASK-1), and mixed lineage kinse-3(MLK-3). The MAPKKKs may be activated by kinasesknown as MAPKKK kinases (MAPKKKKs), one of which isp21-activated kinase (PAK). In addition to these kinases,low molecular weight GTP-binding (LMWG) proteins reg-ulate the activity of MAPKKKs and MAPKKKKs [2,4].There are several different families of LMWG proteins, twoof which include the Ras (N-Ras, K-Ras, and H-Ras) andRho (Rac 1, 2 and 3, Cdc42 and Rho A, B and C) families.The activated MAPKs phosphorylate a large number ofboth cytoplasmic and nuclear proteins, exerting their spe-cific functions. For example, activated ERK1/2 phosphor-ylate ternary complex factor (TCF) proteins such as Elk-1and SAP-1, which form transcriptional complexes withserum response factor (SRF) in the promoter region ofearly response genes (e.g. c-fos, egr-1, junB) and therebyregulate their expression [7]. As shown in Fig. 1, many ofthese nuclear proteins, as a result of their ability to modu-late expression of other proteins, are potential candidatesfor critical factors involved in the cellular response tostimuli.It appears that the majority of ovarian tumors arise fromthe ovarian surface epithelium (OSE), which is a simplesquamous-to-cuboidal mesothelium covering the ovary[8]. As mentioned earlier, the MAPK cascade can be acti-vated via both RTKs and GPCRs, which include the recep-tors of growth factors, gonadotropins and gonadotropin-releasing hormones (GnRH). In ovarian cancer cells,MAPKs are activated and regulated by cisplatin [9], paclit-axel [10], endothelin-1 [11] and GnRH [12] suggestingthat the MAPK signaling pathway plays an important rolein the regulation of proliferation, survival and apoptosisin response to these external stimuli in ovarian cancer. Inthis review, we summarize the activation of the MAPK andits signaling cascade induced by hormones, growth factorsand chemotherapeutic agents in normal and (pre)neo-plastic OSE cells.Activation of MAPK by hormonal factorsThere is increasing evidence that gonadotropin-releasinghormone (GnRH) and its agonists (GnRHa) may play acritical role in the inhibition of cell proliferation in gyne-cological cancers including ovarian and endometrial can-cers. However, their biological mechanism remains to beuncovered. The GnRH receptor (GnRH-R) belongs to thefamily of GPCRs. MAPK has been implicated in the anti-proliferative effect of GnRHa in CaOV-3 ovarian cancercell line [12]. Treatment of CaOV-3 cells with GnRHaresulted in an activation of ERK at 5 min, reached thehighest activation at 3 h and sustained until 24 h, whereasGnRHa had no effect on the activation of the JNK. In addi-observed following GnRHa treatment. Treatment with aninhibitor of mitogen-activated protein/ERK kinase,PD98059 reversed the antiproliferative effect of GnRHaand the GnRH-induced dephosphorylation of the retino-blastoma protein. These results indicate that an activationof ERK may play a role in the antiproliferative effect ofGnRHa [12]. In our laboratory, we have shown that anagonist of GnRH (D-Ala6)-GnRH, induced a biphasic pat-tern of ERK-1/-2 activation in OVCAR-3 cells (Fig. 2). Alow concentration of GnRHa (10-10 M) resulted in a signif-icant decrease of MAPK activity, whereas high concentra-tions (10-7 and 10-6 M) induced an activation of MAPKpathway in ovarian and placental cells [13]. It is of interestto note that GnRH signaling appears to involve ERK-1/-2phosphorylation through the activation of adenylylcyclase and PKC in rat luteinized ovarian tumors [14].An involvement of gonadotropins, follicle-stimulatinghormone (FSH) and luteinizing hormone (LH), has beenThe effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian ancer lineFigure 2The effect of GnRH on ERK-1/-2 (p44/p42) activation in ovarian cancer line. The phosphorylated form (P-MAPK) nor-malized 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]Page 3 of 8(page number not for citation purposes)tion, the ERK kinase was also activated and an increase inphosphorylation of son of sevenless (Sos), and Shc wasproposed in the progression and metastasis of ovariancancer. Expression of FSH receptor (FSH-R), a member ofReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71the GPCRs family, has been demonstrated in normal OSE[15], ovarian inclusions and epithelial tumors [16], impli-cating a potential role of FSH in these cells. Treatmentwith FSH resulted in a growth-stimulation in ovarian can-cer cells in a dose- and time-dependent manner in vitro[16,17]. Despite these findings, the precise molecularunknown. In a recent study, we have investigated theinvolvement 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) resultedin the MAPK activation of immortalized OSE (IOSE-29)Effect of FSH in the presence or absence of PD98059 on RK-1/-2 (p44/p42) activationFigure 3Effect 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]IOSE-291        2        3        4        5        6        7p44p42p44p42T-MAPKP-MAPK050100150200    FSH       0        10     100   1000   100    100       0    ng/mlPD98059   0         0        0     0        0       50      50 PMa aaaaa,bTreatment with FSH and/or PD98059MAPK Activity (% Control)Effect of FSH in the presence or absence of PD98059 on RK-1/-2 (p44/p42) activationFigure 4Effect 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 time-dependent manner by immu-noblot 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 con-trol; b, P < 0.05 vs. FSH (100 ng/ml) treatment for 10 min. 1, untreated control; 2, FSH (100 ng/ml) treatment for 5 min; 3, FSH (100 ng/ml) treatment for 10 min; 4, FSH (100 ng/ml) treatment for 20 min; 5, FSH (100 ng/ml) treatment for 60 min; 6, FSH (100 ng/ml) plus PD98059 (50 µM) treatment for 10 min; 7, PD98059 (50 µM) treatment. [Reproduced, per-mission with, from: Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC; "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovar-ian surface epithelial cells" in: J Clin Endocrinol Metab 2002, 87:2245–2253. Copyright from Endocrine Society]IOSE-291       2        3         4       5         6         7T-MAPKP-MAPKp44p42p44p420100200          Time   0        5  10      20       60      10      10   min    FSH       0   100  100  100 100 100    0  ng/mlPD98059   0 0     0 0    0       50      50 PMaaa,bTreatment with FSH and/or PD98059MAPK Activity (% Control)aPage 4 of 8(page number not for citation purposes)mechanism of FSH in terms of growth stimulation andintracellular signaling in ovarian cancer remainedcells as shown in Fig. 3. The stimulatory effect of FSH inthe cellular proliferation and MAPK activation was com-Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71pletely abolished in the presence of PD98059, a MEKinhibitor (Fig. 3). In IOSE-29 cells, treatment with FSHsignificantly increased MAPK activity at 5–10 min, and anactivated MAPK declined to control level after 20 min inthese cells (Fig. 4). In addition, treatment with FSHresulted in substantial phosphorylation of Elk-1, the Etsfamily transcriptional factor [18]. These results supportthe hypothesis that the MAPK cascade is involved in cellu-lar function such as growth stimulation in response toFSH in pre-neoplastic OSE cells.Similar to FSH, adenosine triphosphate (ATP) has beenimplicated in the regulation of cell proliferation and acti-tors and extracellular ATP has been suggested to play arole in cellular proliferation and intracellular calciumconcentrations (Ca2+) in ovarian cancer cells [19,20]. Ourrecent results indicated that treatment with ATP resultedin an activation of ERK-1/-2 in IOSE-29 cell line as seenFig. 5[21]. The stimulatory effect of ATP in the cellularproliferation and MAPK activation was completely abol-ished in the presence of PD98059 and staurosporin (aPKC inhibitor), suggesting that the growth stimulatoryeffect of ATP is mediated via PKC-dependent MAPK acti-vation in pre-neoplastic OSE cells (Fig. 5). Treatment withATP resulted in substantial phosphorylation of Elk-1, fur-ther implicating the MAPK cascade in the growth stimula-tory effect of ATP in pre-neoplastic OSE cells [21].Activation of MAPK by growth factors and cytokinesEndothelin-1 (ET-1) is a potential autocrine regulatoryfactor in ovarian cancer. Treatment of OVCA 433 ovariancancer with ET-1 resulted in a phosphorylation of ERK-2and mitogenic responses. The epidermal growth factorreceptor (EGF-R)/ras-dependent pathway may contributeto the activation of MAPK/ERK-2 and mitogenic signalinginduced by ET-1 in these cells, suggesting that ET-1induced activation of MAPK is mediated in part by signal-ing pathways that are initiated by transactivation of theEGF-R [11]. As autocrine regulators, lysophosphatidicacid (LPA) and sphingosine-1-phosphate (S1P) have beendemonstrated to activate MAPK kinase (MEK) and p38MAPK via AKT pathway in HEY ovarian cancer cells. Thekinase activity and S473 phosphorylation of Akt inducedby LPA and S1P required both MEK and p38 MAPK, andMEK is likely to be upstream of p38 in these cells,suggesting that the requirement for both MEK and p38 iscell type- and stimulus-specific [22]. In rhesus ovarian sur-face epithelial cells in culture, treatment with extracellularcalcium induced an activation of MAPK in the response tocell proliferation in these normal cells [23]. Human inter-leukin-8 (IL-8) rapidly activated ERK-1/-2 pathway viastimulation of the CXCR-1/2 receptors [24]. By usinginhibitors such as genestein and herbimycin A, tyrosinekinases have been shown to be involved in the IL-8 activa-tion of ERK-1/-2 in SKOV-3 cells, suggesting an importantcross-talk between the chemokine and growth factor path-ways in the migration and proliferation in ovarian cancercells [24].In addition to ERK1/2, the JNK pathway has been sug-gested to play a role in the cell proliferation and apoptosisin ovarian cancer. For instance, treatment with tumornecrosis factor (TNF) alpha activated ERK1/2 at 10–20min, and a maximum threefold induction of ERK1/2activity was observed after 1 min of treatment [25]. Inhi-Effect of ATP on ERK-1/-2 (p44/p42) and Elk-1 in the absence or presence of PD98059 and staurosporinFigure 5Effect of ATP on ERK-1/-2 (p44/p42) and Elk-1 in the absence or presence of PD98059 and staurosporin. To examine the role of ATP on MAPKs in IOSE-29, the cells were pretreated with 50 µM PD98059 or 0.1 µM staurosporin for 30 min, fol-lowed by treatment with 100 µM ATP for 10 min. The P-MAPK normalized by T-MAPK was analyzed by immunoblot analysis, and Elk-1, a downstream pathway of ERK-1/-2, was measured by in vitro MAPK assay, respectively. [Reproduced, permission with, from: Choi K-C, Tai C-J, Tzeng C-R, Auer-sperg N, Leung PC; "Adenosine triphosphate (ATP) activates mitogen-activated protein kinases (MAPKs) in neoplastic ovarian surface epithelium (OSE) cells" in: Biol Reprod 2003, 68: 309–315. Copyright from Society for the Study of Reproduction]+       +         -+        - ATP (100 uM)Cnt DMSO -+        +         -- PD98059 (50 uM) ---+       + Staurosporin (0.1 uM )IOSE-29p44p42p44p42T-MAPKP-MAPK-+                +                 + ATP (100 uM)--+                 - PD98059 (50 uM)- - - + Staurosporin (0.1 uM )IOSE-29Elk-1Page 5 of 8(page number not for citation purposes)vation of MAPK pathway in ovarian cancer cells. ATPbinds to heterotrimeric G protein-coupled P2 purinocep-bition of TNF alpha-induced ERK1/2 activity by PD98059was associated with induction of apoptosis in the TNFReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subse-quent transient increase in TNF alpha-induced JNK1 activ-ity. These results indicate that ERK1/2 activity maymodulate cellular response to TNF alpha. A balancebetween ERK1/2 and JNK1 activation may be pivotal inthe cellular growth and apoptosis response to TNF alpha[25].Activation of MAPK by chemotherapeutic agentsCisplatin has been widely used as a chemotherapeuticagent to treat ovarian cancers, although its use is some-what limited because of cisplatin-resistance. The molecu-lar mechanism of cisplatin-induced biological effect inovarian cancer is not well understood. Cisplatin caused alate and prolonged induction of both ERK1/2 and JNK1activity in a dose-dependent manner, whereas no signifi-cant difference was observed in p38 activity in SKOV-3cells [9]. These results suggest that ERK and other signaltransduction pathways may play a role in response to cis-platin and be important for the development of new strat-egies to enhance the therapeutic use of platinum drugs. Incisplatin-resistant CaOV-3 and cisplatin-sensitive A2780ovarian cancer cells, cisplatin induced an activation ofboth ERK and JNK in distinct time and dose patterns [26].Cisplatin-induced JNK activation was neither extracellularand intracellular Ca2+-dependent nor protein kinase C-dependent, whereas cisplatin-induced ERK activation wasextracellular and intracellular Ca2+-dependent and pro-tein kinase C-dependent [26]. In regard to the regulationof apoptosis by cisplatin, it has been shown that cisplatinactivated a robust apoptotic pathway involved in the acti-vation of JNK and p38 MAPK in cisplatin-sensitive ovar-ian cancer cells, whereas it fails to elicit the response incisplatin-resistant 2008/C13 cells [27]. In cisplatin-resist-ant cells, the proteolytic activation of MEKK1 by caspase-3 is deficient, suggesting that inadequate caspase-3processing and MEKK1 activation may induce a cisplatin-resistant phenotype [27].The activation of two MAP kinases, JNK1 and ERK1/2 wascompared in the cisplatin-sensitive ovarian carcinoma cellline A2780 and the cisplatin-resistant cell lines CP70 andC200 [28]. Distinct patterns of cisplatin-induced JNK1and ERK1/2 activation were observed in the cell lines withdifferent levels of cisplatin sensitivity, and inhibition ofcisplatin-induced ERK1/2 activation appeared to enhancesensitivity to cisplatin in both cisplatin-sensitive and cis-platin-resistant cell lines. It appears that these MAPK path-ways may be important in the cisplatin-resistance inovarian cancer, which can be used as a potential therapeu-tic strategy [28]. More recent data indicate that cisplatintion and the cisplatin-resistant cells showing onlytransient (1–3 h) activation of JNK and p38 [29]. In addi-tion, the inhibition of cisplatin-induced JNK and p38 acti-vation blocked cisplatin-induced apoptosis and persistentactivation of JNK resulted in an increase in the phosphor-ylation of c-Jun transcription factor, which stimulated atranscription of an immediate downstream target, a deathinducer Fas ligand (FasL) in cisplatin-sensitive cells. Thus,it appears that the JNK-c-Jun-FasL-Fas signaling pathwayplays an important role in the regulation of cisplatin-induced apoptosis in ovarian cancer cells, and the dura-tion of JNK activation may be essential in the determina-tion of survival or apoptosis in ovarian cancer cells [29].Taxol, a microtubule stabilizer, is a useful therapeuticagent for ovarian cancer treatment. Treatment with taxolresulted in an activation of ERK1/2 and p38 MAPK inhuman ovarian carcinoma cells with distinct kinetics [30].The low concentrations of taxol (1–100 nM) activatedERK1/2 within 0.5–6 h, whereas a longer exposure (24 h)at low concentrations abrogated ERK1/2 phosphoryla-tion/activation. Higher concentrations (1–10 µM) of taxolresulted in a sharp inhibition of ERK1/2 activity, whereassame concentrations activated p38 kinase at 2 – 24 h,indicating that the activation of MAPK may be dependenton the dose and exposure time of chemotherapeutic agent[30]. Interestingly, treatment with paclitaxel resulted in aphosphorylation of p70S6K (T421/S424) and this paclit-axel-induced phosphorylation requires both de novo RNAand protein synthesis via multiple signaling pathwaysincluding ERK1/2 MAP kinase, JNK, PKC, Ca(++), PI3K,and mammalian target of rapamycin (mTOR). Thus, pacl-itaxel is able to induce p70S6K phosphorylation and exertits antitumor effect via multiple signaling pathways, espe-cially inhibition of p70S6K [31].Genes related with the activation of MAPKThe expression levels of kinases have compared in nor-mal, immortalized and neoplastic OSE cells [32]. Theexpression levels of casein kinase II (CK2), p38 MAPK,cyclin-dependent kinase, and the phosphatidylinositol 3-kinase (PI3K) effectors Akt2 and p70 S6 kinase (S6K) wereseveral-fold higher in neoplastic OSE than in normal OSE,whereas no significant difference was observed in theexpression of ERK1/2 [32]. Interestingly, c-Jun NH2-kinase but not PI3-K resulted in telomerase activity. Aninhibition of JNK by a specific inhibitor reversed telomer-ase activity, while the expression of JNK induced an acti-vation of a reporter gene fused to the hTERT promotersequence at transcriptional level, indicating that JNK playsa critical role in the regulation of telomerase activity andmay provide possible therapeutic approaches to ovariancancer [33]. In addition, the correlation between BRCA1Page 6 of 8(page number not for citation purposes)differentially induced JNK and p38 pathways, with the cis-platin-sensitive cells showing prolonged (8–12 h) activa-and stress-associated MAPK has been proposed in ovariancancer cells [34]. The JNK, an apoptotic signalingReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71pathway, was induced by overexpression of BRCA1, andBRCA1 enhanced the signaling pathways that sequentiallyinvolved H-Ras, MEKK4, JNK, Fas ligand/Fas interactions,and caspase-9 activation [34].Recently, it has been shown that gamma-synuclein is dra-matically up-regulated in the vast majority of late-stagebreast and ovarian cancers and its overexpression may berelated with enhanced tumorigenicity. Furthermore, over-expression of gamma-synuclein resulted in a constitutiveactivation of ERK1/2 and down-regulation of JNK1 inresponse to environmental stress signals, including UV,arsenate and heat shock [35]. The cross-talk between theMAPK signaling pathway and multi-drug resistant proteinMDR-1 has been suggested in terms of sensitivity or resist-ance to chemotherapy. A constitutive activation of theERK1/2 pathway was observed, whereas the level of activeJNK and p38 remained unchanged in the taxol resistantcells. Inhibition of the ERK1/2 pathway by specific inhib-itors, UO126 or PD098059, resulted in a re-sensitizationin the taxol resistant cells [36].There is some evidence that the MAPK pathway may playa role in the metastasis of ovarian cancer. Treatment of9 secretion activated by fibronectin (FN), suggesting animportance of these signaling molecules as a chemothera-peutic target for cancer to prevent metastasis [37]. Theurokinase-type plasminogen activator receptor (u-PAR)has been implicated in tumor progression, and the expres-sion of this gene is strongly up-regulated by phorbol 12-myristate 13-acetate (PMA), a PKC activator. Treatment ofthe u-PAR-deficient ovarian cancer OVCAR-3 cells, whichcontain low JNK activities, with PMA resulted in a rapid (5min) activation of JNK pathway. This finding suggests thatthe PMA- or c-Ha-Ras-dependent stimulation of u-PARgene expression requires a JNK1-dependent signalingmodule [38].Concluding RemarksThere is increasing evidence that the three well-character-ized members of the MAPK family, ERK1/2, JNK/SAPKand p38, play an important role in the regulation of pro-liferation, survival and apoptosis in ovarian cancer inresponse to the external stimuli including hormones,growth factors, cytokines and chemotherapeuticchemicals. The signaling pathways by which hormonessuch as FSH, ATP and GnRH exert their effects in the reg-ulation of cell proliferation and apoptosis in ovarian can-cer cells are proposed in Fig. 6. As well, MAPK pathwaysmay contribute to the metastasis and chemoresistance ofovarian cancer. A better understanding of the MAPK andother signaling pathways in normal and neoplastic OSEwill provide new insights for the development of noveltherapeutic approach to ovarian cancer.AcknowledgmentsPCKL 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.References1. Davis RJ: MAPKs: new JNK expands the group. Trends BiochemSci 1994, 19:470-473.2. Johnson GL and Lapadat R: Mitogen-activated protein kinasepathways mediated by ERK, JNK, and p38 protein kinases.Science 2002:1911-1912.3. Cobb MH and Goldsmith EJ: How MAP kinases are regulated. JBiol Chem 1995, 270:14843-14846.4. Fanger GR: Regulation of the MAPK family members: Role ofsubcellular localization and architectural organization. HistolHistopathol 1999, 14:887-894.5. Garrington T and Johnson GL: Organization and regulation ofmitogen-activated protein kinase signaling pathway. 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Persons DL, Yazlovitskaya EM, Cui W and Pelling JC: Cisplatin-Activation of the MAPK signaling pathway by FSH, ATP and GnRH n ovarian cancerFigure 6Activation of the MAPK signaling pathway by FSH, ATP and GnRH in ovarian cancer.Stimulatory pathwayInhibitory pathwayFSHGnRHFSH-RGnRH-RCytoplasmNucleusERK1/2Apoptosisp38JNK/SAPKDifferentiationProliferation MetastasisMEK1/2MAPKK 3/6MAPKK 4/7PD98059 SB203580P2U-RATPGnRH-inducedsignals?Elk-1AP-1SB600125Page 7 of 8(page number not for citation purposes)ovarian cancer cells with MEK1 inhibitors, U0126 andPD98059, induced a significant suppression of the MMP-induced activation of mitogen-activated protein kinases inovarian carcinoma cells: inhibition of extracellular signal-Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/71regulated kinase activity increases sensitivity to cisplatin. 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