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This Article Full Text Full Text (PDF) All Versions of this Article: 68/1/309    most recent biolreprod.102.006551v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Choi, K.-C. Articles by Leung, P. C.K. Search for Related Content PubMed PubMed Citation Articles by Choi, K.-C. Articles by Leung, P. C.K. Agricola Articles by Choi, K.-C. Articles by Leung, P. C.K.

Adenosine Triphosphate Activates Mitogen-Activated Protein Kinase in Pre-Neoplastic and Neoplastic Ovarian Surface Epithelial Cells¹

^a Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 ^c Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5 ^b Taipei Medical University Hospital, Taipei 110, Taiwan

To investigate the role of ATP in ovarian tumorigenesis, the present study examined the expression of the P2U purinoceptor (P2U-R) and effect of ATP on growth stimulation in pre-neoplastic and neoplastic ovarian surface epithelial (OSE) cells. The immortalized OSE (IOSE) cell lines, including IOSE-29 (pre-neoplastic), IOSE-29EC (neoplastic), and OVCAR-3 (ovarian adenocarcinoma cell line) were used. Our results indicated that P2U-R mRNA was expressed and that ATP exerted a growth-stimulatory effect in IOSE-29, IOSE-29EC, and OVCAR-3. To investigate the mechanism of the growth-stimulatory effect, the activation of mitogen-activated protein kinases (MAPKs) by ATP was examined. Treatment with ATP resulted in MAPK activation in IOSE-29 and IOSE-29EC cells, whereas the stimulatory effect of ATP in cellular proliferation and MAPK activation was completely abolished in the presence of PD98059 (an MAPK/ERK kinase inhibitor) and staurosporin (a protein kinase C inhibitor), suggesting that the growth stimulatory effect of ATP is mediated via protein kinase C-dependent MAPK activation in pre-neoplastic and neoplastic OSE cells. In a time-dependent study, ATP significantly increased MAPK activity at 5–20 min in IOSE-29 cells. Activated MAPK declined to control levels after 20 min in these cells. Treatment with ATP significantly induced MAPK activation after 5 min and was sustained for 60 min in IOSE-29EC cells. In addition, treatment with ATP resulted in substantial phosphorylation of Elk-1, the Ets family transcriptional factor, confirming that ATP action is mediated by activation of MAPK. In conclusion, we have demonstrated that P2U-R was expressed and that ATP induced growth stimulation in IOSE and OVCAR-3 cells. Furthermore, treatment with ATP resulted in the activation of an MAPK cascade and phosphorylation of Elk-1 in IOSE-29 and IOSE-29EC cells. These results suggest that the MAPK cascade may be involved in growth stimulation in response to ATP in pre-neoplastic and neoplastic OSE cells.

¹ This work was supported by grants from the Canadian Institutes of Health Research (CIHR). P.C.K.L. is recipient of a Distinguished Scholar award from the Michael Smith Foundation for Health Research.

² Correspondence: Peter C.K. Leung, Department of Obstetrics and Gynecology, University of British Columbia, 2H-30, 4490 Oak St., Vancouver, BC, Canada V6H 3V5. FAX: 604 875 2717; peleung{at}interchange.ubc.ca