Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness
Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closel...
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doaj-6474678a02ef4d84b24ace6e1ee5d2e82021-06-01T00:34:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01225374537410.3390/ijms22105374Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer AggressivenessBo Young Jeong0Kyung Hwa Cho1Se-Hee Yoon2Chang Gyo Park3Hwan-Woo Park4Hoi Young Lee5Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, KoreaDepartment of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, KoreaDivision of Nephrology and Department of Internal Medicine, College of Medicine, Daejeon 35365, KoreaDepartment of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, KoreaDepartment of Cell Biology, College of Medicine, Konyang University, Daejeon 35365, KoreaDepartment of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, KoreaLysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.https://www.mdpi.com/1422-0067/22/10/5374lysophosphatidic acidautotaxindiscoidin domain receptor 2Twist1ovarian cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bo Young Jeong Kyung Hwa Cho Se-Hee Yoon Chang Gyo Park Hwan-Woo Park Hoi Young Lee |
spellingShingle |
Bo Young Jeong Kyung Hwa Cho Se-Hee Yoon Chang Gyo Park Hwan-Woo Park Hoi Young Lee Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness International Journal of Molecular Sciences lysophosphatidic acid autotaxin discoidin domain receptor 2 Twist1 ovarian cancer |
author_facet |
Bo Young Jeong Kyung Hwa Cho Se-Hee Yoon Chang Gyo Park Hwan-Woo Park Hoi Young Lee |
author_sort |
Bo Young Jeong |
title |
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness |
title_short |
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness |
title_full |
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness |
title_fullStr |
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness |
title_full_unstemmed |
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness |
title_sort |
discoidin domain receptor 2 mediates lysophosphatidic acid-induced ovarian cancer aggressiveness |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion. |
topic |
lysophosphatidic acid autotaxin discoidin domain receptor 2 Twist1 ovarian cancer |
url |
https://www.mdpi.com/1422-0067/22/10/5374 |
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