Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3
Phosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiolo...
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MDPI AG
2023-06-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/7/1804 |
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| author | Ana Gomez-Larrauri Patricia Gangoiti Laura Camacho Natalia Presa Cesar Martin Antonio Gomez-Muñoz |
| author_facet | Ana Gomez-Larrauri Patricia Gangoiti Laura Camacho Natalia Presa Cesar Martin Antonio Gomez-Muñoz |
| author_sort | Ana Gomez-Larrauri |
| collection | DOAJ |
| description | Phosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiological actions are incompletely understood. In the present work, we demonstrate that PA stimulates the migration of the human non-small cell lung cancer (NSCLC) A549 adenocarcinoma cells, as determined by the transwell migration assay. PA induced the rapid phosphorylation of mitogen-activated protein kinases (MAPKs) ERK1-2, p38, and JNK, and the pretreatment of cells with selective inhibitors of these kinases blocked the PA-stimulated migration of cancer cells. In addition, the chemotactic effect of PA was inhibited by preincubating the cells with pertussis toxin (PTX), a Gi protein inhibitor, suggesting the implication of a Gi protein-coupled receptor in this action. Noteworthy, a blockade of LPA receptor 1 (LPA1) with the specific LPA1 antagonist AM966, or with the selective LPA1 inhibitors Ki1645 or VPC32193, abolished PA-stimulated cell migration. Moreover, PA stimulated the phosphorylation of the transcription factor STAT3 downstream of JAK2, and inhibitors of either JAK2 or STAT3 blocked PA-stimulated cell migration. It can be concluded that PA stimulates lung adenocarcinoma cell migration through an interaction with the LPA1 receptor and subsequent activation of the MAPKs ERK1-2, p38, and JNK, and that the JAK2/STAT3 pathway is also important in this process. These findings suggest that targeting PA formation and/or the LPA1 receptor may provide new strategies to reduce malignancy in lung cancer. |
| first_indexed | 2024-03-11T01:17:13Z |
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| id | doaj.art-fc9c4fc296574930a0aa29c840786590 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T01:17:13Z |
| publishDate | 2023-06-01 |
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| series | Biomedicines |
| spelling | doaj.art-fc9c4fc296574930a0aa29c8407865902023-11-18T18:25:11ZengMDPI AGBiomedicines2227-90592023-06-01117180410.3390/biomedicines11071804Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3Ana Gomez-Larrauri0Patricia Gangoiti1Laura Camacho2Natalia Presa3Cesar Martin4Antonio Gomez-Muñoz5Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, SpainPhosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiological actions are incompletely understood. In the present work, we demonstrate that PA stimulates the migration of the human non-small cell lung cancer (NSCLC) A549 adenocarcinoma cells, as determined by the transwell migration assay. PA induced the rapid phosphorylation of mitogen-activated protein kinases (MAPKs) ERK1-2, p38, and JNK, and the pretreatment of cells with selective inhibitors of these kinases blocked the PA-stimulated migration of cancer cells. In addition, the chemotactic effect of PA was inhibited by preincubating the cells with pertussis toxin (PTX), a Gi protein inhibitor, suggesting the implication of a Gi protein-coupled receptor in this action. Noteworthy, a blockade of LPA receptor 1 (LPA1) with the specific LPA1 antagonist AM966, or with the selective LPA1 inhibitors Ki1645 or VPC32193, abolished PA-stimulated cell migration. Moreover, PA stimulated the phosphorylation of the transcription factor STAT3 downstream of JAK2, and inhibitors of either JAK2 or STAT3 blocked PA-stimulated cell migration. It can be concluded that PA stimulates lung adenocarcinoma cell migration through an interaction with the LPA1 receptor and subsequent activation of the MAPKs ERK1-2, p38, and JNK, and that the JAK2/STAT3 pathway is also important in this process. These findings suggest that targeting PA formation and/or the LPA1 receptor may provide new strategies to reduce malignancy in lung cancer.https://www.mdpi.com/2227-9059/11/7/1804phosphatidic acidlysophosphatidic acid receptorslung cancer cell migrationmitogen-activated protein kinasesJanus kinasesignal transducer and activator of transcription |
| spellingShingle | Ana Gomez-Larrauri Patricia Gangoiti Laura Camacho Natalia Presa Cesar Martin Antonio Gomez-Muñoz Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 Biomedicines phosphatidic acid lysophosphatidic acid receptors lung cancer cell migration mitogen-activated protein kinases Janus kinase signal transducer and activator of transcription |
| title | Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 |
| title_full | Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 |
| title_fullStr | Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 |
| title_full_unstemmed | Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 |
| title_short | Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3 |
| title_sort | phosphatidic acid stimulates lung cancer cell migration through interaction with the lpa1 receptor and subsequent activation of map kinases and stat3 |
| topic | phosphatidic acid lysophosphatidic acid receptors lung cancer cell migration mitogen-activated protein kinases Janus kinase signal transducer and activator of transcription |
| url | https://www.mdpi.com/2227-9059/11/7/1804 |
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