Hypoxic tumor microenvironment plays a major role in promoting cancer progression. Recent studies have identified a crucial role for miRNAs in hypoxia-induced cancer growth. In breast cancer, it has been shown that EGFR inhibits the maturation of specific, tumor-suppressing, miRNAs via the tyrosine-phosphorylation of argonaute-2 (AGO2) to evade cell death during hypoxia. In the case of ovarian cancer, lysophosphatidic acid (LPA) has been shown to be critically involved in the hypoxic response of ovarian cancer cells. Therefore, we hypothesized that LPA stimulates the phosphorylation of AGO2 during hypoxia to prevent the maturation of miRNAs involved in suppressing ovarian cancer progression. The specific aim of this project is to test this hypothesis by investigating 1) whether LPA stimulates the phosphorylation of AGO2 and 2) whether such phosphorylation is hypoxia specific. Serum starved SKOV3IP and HeyA8 cells (1 x 106) were stimulated with 10% FBS or 20 �M LPA under hypoxia (1% O2) or normoxia for 24 hours. AGO2 was immunoprecipitated from the respective cell lysates and subjected to immunoblot analyses using specific antibodies to phosphoserine and AGO2. Results indicate that FBS stimulates the Ser/Thr-phosphorylation of AGO2 under both normoxia and hypoxia, whereas LPA stimulates Ser/Thr-phosphorylation of AGO2 only under hypoxia. The present study is the first to report a role for LPA in Ser/Thr-phosphorylation of AGO2. Further studies should define the pathological role of LPA in modulating miRNA biogenic machinery in ovarian cancer.

LPA stimulates Ser/Thr-phosphorylation of argonaute-2 in hypoxia-stressed ovarian cancer cells

247th National Meeting (2014)

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