- Open Access
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.
- signaling pathway
- ovarian cancer
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.
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 .
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 .
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.
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