Reactive Oxygen Species are Second Messengers in the Lysophosphatidic Acid Induced Survival Signaling of Ovarian Cancer

Abstract

One of the essential aspects of the pathological nature of ovarian cancer is the activity of lysophosphatidic acid (LPA), a constitutively produced lipid mediator that is a potent agonist of signaling cascades that promote tumor growth and survival, including the PI3K/ Akt, MAPK/ ERK, and NF-κB pathways. We found that these signaling cascades are increased in SKOV3 ovarian carcinoma cells when stimulated with LPA. Furthermore, each of these pathways is positively regulated by reactive oxygen species (ROS), which are becoming increasingly recognized as having signaling capabilities. We observed that LPA causes increased ROS production in SKOV3 cancer cells, which led us to question if ROS served as second messengers in the aforementioned survival signaling pathways. We challenged SKOV3 cells with antioxidant treatments in the presence of LPA to examine their effects on cell proliferation and Akt, ERK, and NF-κB activation. Two antioxidants, N-acetyl-cysteine (NAC), curcumin, and EUK-134 each considerably reduced cell proliferation, as well as NF-κB activity. EUK-134 also diminished LPA-stimulated Akt and ERK activation. We observed that these signaling pathways were similarly abolished by diphenyleneiodonium chloride (DPI), a compound that is known to inhibit NADPH oxidase, a primary source of ROS in non-phagocytic cells. Finally, we found that DPI decreased LPA stimulated ROS production in our model ovarian cancer cell line. Our findings revealed that ROS is a necessary signaling component in the survival response of SKOV3 cells to LPA activation. Likewise, we demonstrated that NADPH oxidase is likely a primary source of ROS generation for intermediate signaling in this model system. From this study, we concluded that antioxidant therapies may prove useful in combination with current treatment regimens to successfully reduce the severity of ovarian cancer.