Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus
Autor: | Danny N. Dhanasekaran, Ji Hee Ha, Muralidharan Jayaraman, Jeremy D. Ward, Yong Sang Song, Rangasudhagar Radhakrishnan |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Slug 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Lysophosphatidic acid metastasis Humans Epithelial–mesenchymal transition HIF1α Transcription factor Ovarian Neoplasms biology EMT Cell migration biology.organism_classification Hypoxia-Inducible Factor 1 alpha Subunit LPA 030104 developmental biology ovarian cancer src-Family Kinases Oncology chemistry 030220 oncology & carcinogenesis Cancer cell Immunology Cancer research lipids (amino acids peptides and proteins) Female Snail Family Transcription Factors Signal transduction Lysophospholipids Proto-oncogene tyrosine-protein kinase Src Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | 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-1α (HIF1α) in SKOV3.ip ovarian cancer cells. HIF1α 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 HIF1α in ovarian cancer cells, with an observed maximum level of HIF1α-induction by 4 hours. Our report demonstrates that LPA stimulates the increase in HIF1α levels via Gαi2. Consistent with the role of HIF1α 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 Gαi2, HIF1α 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 HIF1α with the clinically used HIF1α inhibitor, PX-478, drastically attenuates LPA-stimulates invasive migration of SKOV3.ip cells. Thus, our present study demonstrates that LPA utilizes a Gαi2-mediated signaling pathway via Src kinase to stimulate an increase in HIF1α levels and downstream EMT-specific factors such as Slug, leading to invasive migration of ovarian cancer cells. |
Databáze: | OpenAIRE |
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