Lysophosphatidic acid induces STAT3 phosphorylation and ovarian cancer cell motility: Their inhibition by curcumin

Seo, Ji‐Hyun; Jeong, Kang Jin; Oh, Woo Jin; Sul, Hae Jeong; Sohn, Jang Sihn; Kim, Yong Kee; Cho, Do Yeun; Kang, Jaeyoung; Park, Chang Gyo; Lee, Hoi Young

doi:10.1016/j.canlet.2009.06.023

Cited by 79 publications

(49 citation statements)

References 28 publications

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“…SKOV3.ip cells were stimulated with LPA for 20 minutes along with the appropriate vehicle control and the lysates were subjected to the transcription array analysis. Our results indicated that LPA stimulation activated several transcription factors that have previously been shown to be stimulated by LPA including STAT3 [7, 31, 32] and CREB [7, 33, 34], thus establishing the functional validity of our array analysis. In addition, we observed that LPA stimulated the activity of HIF1α by 150-fold compared to the untreated control cells and its activation far exceeded the activation of any other transcription factor on the array (Figure 1A).…”

Section: Resultssupporting

confidence: 71%

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Ward

Radhakrishnan

et al. 2016

Oncotarget

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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.

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Section: Resultssupporting

confidence: 71%

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Ward

Radhakrishnan

et al. 2016

Oncotarget

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“…Cell migration assays were performed in triplicates using a 48-well microchemotaxis chamber as described previously (Seo et al, 2010). Briefly, trypsinized cells were resuspended at a density of 2 Â 10 6 cells/ml in RPMI 1640 with 0.1% bovine serum albumin.…”

Section: Rho Activation Assaymentioning

confidence: 99%

The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion

et al. 2012

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“…They demonstrated the role of STAT3 in IL6 mediated migration of the cancer cells through EMT [21]. Seo et al showed that LPA, which plays a primordial role in the occurrence of metastatic lesions in ovarian cancer, also activates STAT3 through secretion of IL6 and IL8 [22]. Meinhold-Heerlein et al demonstrated that G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression [23].…”

Section: Discussionmentioning

confidence: 99%

Copy Number Variation Analysis of Matched Ovarian Primary Tumors and Peritoneal Metastasis

et al. 2011

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Ovarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. Despite initial chemosensitivity and improved surgical procedures, abdominal recurrence remains an issue and results in patients' poor prognosis. Transcriptomic and genetic studies have revealed significant genome pathologies in the primary tumors and yielded important information regarding carcinogenesis. There are, however, few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. We used high-density SNP arrays to investigate copy number variations in matched primary and metastatic ovarian cancer from 9 patients. Here we show that copy number variations acquired by ovarian tumors are significantly different between matched primary and metastatic tumors and these are likely due to different functional requirements. We show that these copy number variations clearly differentially affect specific pathways including the JAK/STAT and cytokine signaling pathways. While many have shown complex involvement of cytokines in the ovarian cancer environment we provide evidence that ovarian tumors have specific copy number variation differences in many of these genes.

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Lysophosphatidic acid induces STAT3 phosphorylation and ovarian cancer cell motility: Their inhibition by curcumin

Cited by 79 publications

References 28 publications

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion

Copy Number Variation Analysis of Matched Ovarian Primary Tumors and Peritoneal Metastasis

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