Blocking LPA-dependent signaling increases ovarian cancer cell death in response to chemotherapy

Abstract

The paradoxical role of reactive oxygen species in cell death versus cell survival establishes a delicate balance between chemotherapy efficacy and management of detrimental side effects. Normal proliferative signaling requires that cells remain inside a redox range that allows reversible protein oxidation to occur. Shifting the redox environment toward highly reducing or oxidizing states leads to cellular stress and cell death. Reactive oxygen species produced in response to Taxol and cisplatin treatment are necessary for effective cancer cell killing but the same ROS leads to damaging side effects in normal tissues. Combining antioxidants with chemotherapeutics to alleviate the unwanted side effects produces variable and often undesirable effects on cancer treatment. Here, we describe a more targeted method to improve ovarian cancer cell killing without the need for antioxidants. In ovarian cancer cells, lysophosphatidic acid (LPA) is a prominent growth factor that contributes to tumor survival and proliferation. We find that blocking LPA-dependent signaling with a specific receptor antagonist consistently increases cell death in response to both Taxol and cisplatin. We propose that inhibiting the upregulated growth factor-dependent signaling in cancer cells will target chemo-insensitivity, potentially lowering the necessary dose of the drugs and preventing harmful side effects.