Lysophosphatidic acid‐induced c‐<i>fos</i> up‐regulation involves cyclic AMP response element‐binding protein activated by mitogen‐ and stress‐activated protein kinase‐1

Lee, Chang-Wook; Kim, Nam-Ho; Choi, Ho-Kyew; Sun, Yuanjie; Nam, Ju-Suk; Rhee, Hae Jin; Chun, Jerold; Huh, Sung‐Oh

doi:10.1002/jcb.21663

Cited by 9 publications

(4 citation statements)

References 39 publications

(56 reference statements)

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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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“…LPA is known for activating different transcription factors, including cFos and STAT3, in different cell lines [ 19 , 20 ], and this was confirmed in MDA-MB-231 and MDA-B02 cells (Figure 5a and 5b ). Because these factors also are regulators of miR-21 expression we evaluated whether cFos and STAT3 could mediate LPA-induced miR-21 expression.…”

Section: Resultsmentioning

confidence: 86%

The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

Sahay

Leblanc

Grünewald³

et al. 2015

Oncotarget

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Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1 in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.

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“…It should be pointed out that while our current study focused on the apoptotic pathways and mechanisms, the LPA effects on cell cycle control and cell proliferation should not be excluded. In fact the PI3K/AKT pathway is known to play an active role in the control of cell cycle [ 35 ]. We found that MEK1 inhibitor (PD98059) significantly inhibited the effect of LPA on the proliferation of Hela cells.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Inhibits Apoptosis Induced by Cisplatin in Cervical Cancer Cells

Sui

Yao

Wang

et al. 2015

BioMed Research International

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Cervical cancer is the second most common cause of cancer death in women worldwide. Lysophosphatidic acid (LPA) level has been found significantly increased in the serum of patients with ovarian, cervical, and colon cancers. LPA level in cervical cancer patients is significantly higher than in healthy controls. LPA receptors were found highly expressed in cervical cancer cells, suggesting LPA may play a role in the development of cervical cancer. The aim of this study is to investigate the effect of LPA on the apoptosis induced by cisplatin (DDP) in cervical cancer cell line and the underlying changes in signaling pathways. Our study found that cisplatin induced apoptosis of Hela cell through inhibiting expression of Bcl-2, upregulating the expression of Bax, Fas-L, and the enzyme activity of caspase-3 (p < 0.05); LPA significantly provided protection against the apoptosis induced by cisplatin by inhibiting the above alterations in apoptotic factor caused by cisplatin (p < 0.05). Moreover, PI3K/AKT pathway was found to be important for the LPA antiapoptosis effect, and administration of PI3K/AKT partially reversed the LPA-mediated protection against cisplatin-induced apoptosis (p < 0.05). These findings have shed new lights on the LPA bioactivity in cervical cancer cells and pointed to a possible sensitization scheme through combined administration of PI3K inhibitor and cisplatin for better treatment of cervical cancer patients, especially those with elevated LPA levels.

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Lysophosphatidic acid‐induced c‐fos up‐regulation involves cyclic AMP response element‐binding protein activated by mitogen‐ and stress‐activated protein kinase‐1

Cited by 9 publications

References 39 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 LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

Lysophosphatidic Acid Inhibits Apoptosis Induced by Cisplatin in Cervical Cancer Cells

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