Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells
Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial mi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/10/2850 |
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| author | Marta Stojak Magdalena Milczarek Anna Kurpinska Joanna Suraj-Prazmowska Patrycja Kaczara Kamila Wojnar-Lason Joanna Banach Martyna Stachowicz-Suhs Joanna Rossowska Ivars Kalviņš Joanna Wietrzyk Stefan Chlopicki |
| author_facet | Marta Stojak Magdalena Milczarek Anna Kurpinska Joanna Suraj-Prazmowska Patrycja Kaczara Kamila Wojnar-Lason Joanna Banach Martyna Stachowicz-Suhs Joanna Rossowska Ivars Kalviņš Joanna Wietrzyk Stefan Chlopicki |
| author_sort | Marta Stojak |
| collection | DOAJ |
| description | Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer–endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells. |
| first_indexed | 2024-03-10T15:53:06Z |
| format | Article |
| id | doaj.art-9e42324b42714e6faec55ffc28fea405 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:53:06Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9e42324b42714e6faec55ffc28fea4052023-11-20T15:54:08ZengMDPI AGCancers2072-66942020-10-011210285010.3390/cancers12102850Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial CellsMarta Stojak0Magdalena Milczarek1Anna Kurpinska2Joanna Suraj-Prazmowska3Patrycja Kaczara4Kamila Wojnar-Lason5Joanna Banach6Martyna Stachowicz-Suhs7Joanna Rossowska8Ivars Kalviņš9Joanna Wietrzyk10Stefan Chlopicki11Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandDepartment of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandDepartment of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, PolandDepartment of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, PolandDepartment of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, PolandLaboratory of Carbofunctional Compounds, Latvian Institute of Organic Synthesis, LV-1006 Riga, LatviaDepartment of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, PolandCancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer–endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.https://www.mdpi.com/2072-6694/12/10/2850protein disulphide isomerase A1adhesiontransendothelial migrationdisulphide exchange |
| spellingShingle | Marta Stojak Magdalena Milczarek Anna Kurpinska Joanna Suraj-Prazmowska Patrycja Kaczara Kamila Wojnar-Lason Joanna Banach Martyna Stachowicz-Suhs Joanna Rossowska Ivars Kalviņš Joanna Wietrzyk Stefan Chlopicki Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells Cancers protein disulphide isomerase A1 adhesion transendothelial migration disulphide exchange |
| title | Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells |
| title_full | Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells |
| title_fullStr | Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells |
| title_full_unstemmed | Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells |
| title_short | Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells |
| title_sort | protein disulphide isomerase a1 is involved in the regulation of breast cancer cell adhesion and transmigration via lung microvascular endothelial cells |
| topic | protein disulphide isomerase A1 adhesion transendothelial migration disulphide exchange |
| url | https://www.mdpi.com/2072-6694/12/10/2850 |
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