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

• Published in: Redox biology 2018-05, Vol.15 (C), p.380-386
• Main Authors: Rogers, LeAnn C., Davis, Ryan R., Said, Naveen, Hollis, Thomas, Daniel, Larry W.
• Format: Article
• Language: English
• Subjects: Antioxidants - metabolism; Apoptosis - drug effects; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Female; Humans; Lysophosphatidic acid (LPA); Lysophospholipids - antagonists & inhibitors; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Paclitaxel - pharmacology; Reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Research Paper; Taxol
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2018.01.002

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. Proliferative signaling occurs inside a window that allows signaling molecules to be reversibly oxidized and reduced. Chemotherapeutic drugs push cells toward a higher oxidation state, which is necessary for effective cancer cell death. The side effect is oxidative damage to normal cells. Antioxidants have a broad range of effects on the oxidative state of normal and cancer cells. While antioxidants may help prevent oxidative damage to normal cells, the effect of the shift in redox state of a given tumor on the efficacy of chemotherapy treatment is variable. Ovarian cancer cells often make and/or respond to increased amounts of LPA, a growth factor found at high levels in ascites fluid. This sustained growth factor-dependent signaling increases cellular survival mechanisms preventing oxidative damage and promoting uncontrolled proliferation. Removing these signals dampens the peak of the survival curve allowing chemotherapeutics to more effectively kill the cancer cells and spare normal tissues. [Display omitted] •Chemotherapy-induced ROS are required for tumor killing, but damag