The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma.
OBJECTIVE
Data regarding signal transduction pathways in human tumors are largely confined to cell line studies to date. We have recently reported on the activation and prognostic role of mitogen-activated protein kinases (MAPK) in ovarian carcinoma in effusions. The objective of the present study was to investigate the expression and clinical role of dual-specificity phosphatases (DUSP), inhibitors of MAPK signaling, in ovarian cancer cells at this site.


METHODS
Thirty-nine fresh frozen malignant effusions from patients diagnosed with serous ovarian carcinoma were studied for mRNA expression of the DUSP MKP-1, MKP-4, MKP-5, and PAC-1 using RT-PCR. DUSP expression was analyzed for possible correlation with patient age, disease stage, tumor grade, histological grade, chemotherapy status, and survival.


RESULTS
MKP-1 and PAC-1 mRNA were found in 36 and 37 effusions, respectively, with expression levels showing considerable variation. MKP-4 and MKP-5 were uniformly absent. MKP-1 showed no association with clinicopathologic parameters. However, PAC-1 expression was significantly higher in effusions obtained before the institution of treatment with both platinum compounds (P = 0.029) and paclitaxel (P = 0.036). In univariate survival analysis, high level of expression of PAC-1 mRNA predicted significantly worse overall survival compared to low expression (mean = 30 vs. 52 months, median = 25 vs. 46 months) (P = 0.007).


CONCLUSIONS
Despite the limited size of this cohort, our results present the first evidence supporting a clinical role for PAC-1 in ovarian carcinoma. In view of the improved outcome associated with activation of all three MAPK families, as well as their elevated expression and activation in post-chemotherapy specimens presented in our previous work, they also suggest that PAC-1 is a true negative regulator of MAPK in ovarian carcinoma cells in effusions.
Givant-Horwitz
Vered
V
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Davidson
Ben
B
Goderstad
Jeanne Mette
JM
Nesland
Jahn M
JM
Tropé
Claes G
CG
Reich
Reuven
R
D001202:Ascitic Fluid / Q000201:enzymology; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D010749:Phosphoprotein Phosphatases; D016066:Pleural Effusion, Malignant / Q000201:enzymology; D011379:Prognosis; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C517019:DUSP1 protein, human; C517032:DUSP2 protein, human; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases