Mitogen-activated protein kinases (MAPK) as predictors of clinical outcome in serous ovarian carcinoma in effusions.
OBJECTIVE
The objective was to investigate the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and high-osmolarity glycerol response kinase (p38), their role in the biology of ovarian carcinoma, and their correlation with chemotherapy response.


METHODS
Sixty-four fresh-frozen effusions from patients diagnosed with serous ovarian carcinoma were studied using immunoblotting. Results were analyzed for possible association with expression of proliferation and apoptosis markers, patient age, disease stage, tumor grade, histological grade, chemotherapy status, and survival.


RESULTS
p38 level correlated with younger age (P = 0.004), while that of JNK correlated with better tumor differentiation (P = 0.009). Higher expression of Pan-JNK (P = 0.018) and higher p-ERK activity (P = 0.014) were seen in postchemotherapy specimens, specifically related to treatment by platinum agents. pan-JNK expression was higher in specimens treated with both platinum agents (P = 0.038) and paclitaxel (P = 0.033). In univariate survival analysis, the level of pan-ERK (P = 0.002), pan-JNK (P = 0.045), and pan-p38 (P = 0.016), as well as p-ERK activity (P = 0.014) correlated with better overall survival. In Cox multivariate survival analysis, pan-ERK (P = 0.001), pan-p38 (P = 0.017), and p-ERK (P = 0.041) retained their predictive value.


CONCLUSIONS
Our results present the first evidence of in vivo involvement of MAPKs in the clinical course of ovarian cancer and the possible effect of chemotherapy on intracellular signaling in this disease. The improved prognosis associated with expression and phosphorylation of all three mitogen-activated protein kinase families highlights the unique properties of cancer cells in effusions and may expand our understanding of the biology of ovarian carcinoma at this site, possibly affecting treatment strategies for this malignancy.
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
Lazarovici
Philip
P
Schaefer
Erik
E
Nesland
Jahn M
JM
Tropé
Claes G
CG
Reich
Reuven
R
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use; D010766:Phosphorylation
D007527:Isoenzymes; D019394:Ki-67 Antigen; D016190:Carboplatin; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D002945:Cisplatin