Deactivation of STAT3 and ERK and Activation of p38 in Ovarian Cancer Cells Treated with a Small Molecule Inhibitor of PTP4A3 Phosphatase.

The Protein Tyrosine Phosphatase of Regenerating Liver-3, also known as PRL-3 or PTP4A3, is among the most oncogenic known protein tyrosine phosphatases, promoting cell migration, survival, metabolism, angiogenesis, and tumor formation. These diverse cancer-associated phenotypic actions are thought to be mediated at least in part by the unique ability of PTP4A3 to function as a positive signal transducer capable of activating STAT3 and ERK1/2 and deactivating p38 kinase. PTP4A3 is significantly upregulated in a majority of human ovarian cancers and is associated with a poor patient prognosis. Our hypothesis is that PTP4A3 phosphatase inhibitors can be effective targeted treatments for ovarian cancer. We previously described a potent, allosteric, small molecule PTP4A3 inhibitor, 7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione, which is also known as KVX-053 or JMS-053. KVX-053 shows no significant in vitro inhibition against a panel of protein kinases or protein tyrosine phosphatases other than PTP4A1-3. KVX-053 is cytotoxic to chemosensitive and chemoresistant human ovarian cancer cell lines in vitro and has in vivo antitumor activity. The goal of the current study was to examine the impact of a PTP4A3 phosphatase inhibitor on human ovarian cancer STAT3, ERK1/2, and p38 activation. We observed a concentration-dependent decrease in the activated form of STAT3, namely, Y705 phospho-STAT3, after a 4 h exposure of A2780 ovarian cancer cells to KVX-053 in vitro. A 4 h exposure to a concentration of KVX-053 that reduced A2780 cell viability by 25% (EC25 ), namely 157 nM, decreased Y705 phospho-STAT3 levels by 46%. An EC50 (470 nM) or EC90 (4.23 μM) concentration decreased Y705 phospho-STAT3 levels by 61% and 87%, respectively. STAT3 levels remained unchanged except for a modest decrease with 4.23 μM of KVX-053. ERK1/2 phosphorylation was decreased 64% with a 4 h treatment of an EC90 concentration of KVX-053 but not with the EC25 or EC50 concentrations. In contrast, KVX-053 caused a concentration-dependent increase in p38 kinase phosphorylation and activation. These results suggest that acute KVX-053 exposure disrupts the PTP4A3/STAT3, PTP4A3/ERK, and PTP4A3/p38 homeostatic loops, providing additional information about the role of PTP4A3 in cancer cell signaling and survival.