Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gai2, Src, and HIF1α signaling nexus

Recent studies have identified a critical role for lysophosphatidic acid (LPA) in the progression of ovarian cancer. Using a transcription factor activation reporter array, which analyzes 45 distinct transcription factors, it has been observed that LPA observed robustly activates the transcription factor hypoxia-induced factor-1 alpha (HIF1 alpha) in SKOV3.ip ovarian cancer cells. HIF1 alpha showed 150-fold increase in its activation profile compared to the untreated control. Validation of the array analysis indicated that LPA stimulates a rapid increase in the levels of HIF1 alpha in ovarian cancer cells, with an observed maximum level of HIF1 alpha-induction by 4 hours. Our report demonstrates that LPA stimulates the increase in HIF1a levels via Gai2. Consistent with the role of HIF1 alpha in epithelial to mesenchymal transition (EMT) of cancer cells, LPA stimulates EMT and associated invasive cell migration along with an increase in the expression levels N-cadherin and Slug/Snail2. Using the expression of Slug/Snail2 as a marker for EMT, we demonstrate that the inhibition of Gai2, HIF1 alpha or Src attenuates this response. In line with the established role of EMT in promoting invasive cell migration, our data demonstrates that the inhibition of HIF1 alpha with the clinically used HIF1 alpha inhibitor, PX-478, drastically attenuates LPA-stimulates invasive migration of SKOV3.ip cells. Thus, our present study demonstrates that LPA utilizes a Gai2-mediated signaling pathway via Src kinase to stimulate an increase in HIF1a levels and downstream EMT-specific factors such as Slug, leading to invasive migration of ovarian cancer cells.