Targeting of PTP4A3 overexpression sensitises HGSOC cells towards chemotherapeutic drugs.

Abstract

Of all the gynecologic malignancies, Ovarian cancer (OC) has the highest mortality rate, partly attributable to its propensity for chemotherapy resistance. The most common sub-type of OC is serous, of which High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal sub-type. Elevated expression of Protein Tyrosine Phosphatase 4 A3 (PTP4A3) is implicated in tumour cell invasion and metastasis, by upregulating the PI3K/Akt/mTORC1 axis. Previously we reported PTP4A3 increased the survival of non-serous OC cells in vitro by activating the autophagy pathway. The present study focused on understanding the impact of PTP4A3 on cell growth, proliferation, and autophagy in HGSOC cells. In particular, we sought to understand whether targeting PTP4A3 in cancer cells that overexpress this phosphatase would sensitise HGSOC cells to existing chemotherapeutic drugs. We report that shRNA-mediated gene silencing of PTP4A3 resulted in the upregulation of compensatory mechanisms that may render PTP4A3 targeting redundant as a monotherapy. However, pan-PTP4A inhibition with JMS-053 overcame this. Finally, silencing of PTP4A3 expression sensitized HGSOC cells to clinically relevant chemotherapeutic drugs. Since mAb therapies targeting PTP4A3 are already in clinical trials, therapeutic targeting of PTP4A3 may have significant value in improving outcomes for those patients with HGSOC, in the clinical setting.