Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells
The use of ultrasound (US) and microbubbles (MB), usually referred to as sonoporation, has great potential to increase the efficacy of chemotherapy. However, the molecular mechanisms that mediate sonoporation response are not well-known, and recent research suggests that cell stress induced by US +...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/11/1058 |
| _version_ | 1827702800624123904 |
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| author | Ragnhild Haugse Anika Langer Elisa Thodesen Murvold Daniela Elena Costea Bjørn Tore Gjertsen Odd Helge Gilja Spiros Kotopoulis Gorka Ruiz de Garibay Emmet McCormack |
| author_facet | Ragnhild Haugse Anika Langer Elisa Thodesen Murvold Daniela Elena Costea Bjørn Tore Gjertsen Odd Helge Gilja Spiros Kotopoulis Gorka Ruiz de Garibay Emmet McCormack |
| author_sort | Ragnhild Haugse |
| collection | DOAJ |
| description | The use of ultrasound (US) and microbubbles (MB), usually referred to as sonoporation, has great potential to increase the efficacy of chemotherapy. However, the molecular mechanisms that mediate sonoporation response are not well-known, and recent research suggests that cell stress induced by US + MBs may contribute to the treatment benefit. Furthermore, there is a growing understanding that the effects of US + MBs are beyond only the cancer cells and involves the tumour vasculature and microenvironment. We treated pancreatic cancer cells (MIA PaCa-2) and stromal cells, fibroblasts (BJ) and human umbilical vein endothelial cells (HUVECs), with US ± MB, and investigated the extent of uptake of cell impermeable dye (calcein, by flow cytometry), viability (cell count, Annexin/PI and WST-1 assays) and activation of a number of key proteins in important intracellular signalling pathways immediately and 2 h after sonoporation (phospho flow cytometry). Different cell types responded differently to US ± MBs in all these aspects. In general, sonoporation induces immediate, transient activation of MAP-kinases (p38, ERK1/2), and an increase in phosphorylation of ribosomal protein S6 together with dephosphorylation of 4E-BP1. The sonoporation stress-response resembles cellular responses to electroporation and pore-forming toxins in membrane repair and restoring cellular homeostasis, and may be exploited therapeutically. The stromal cells were more sensitive to sonoporation than tumoural cells, and further efforts in optimising sonoporation-enhanced therapy should be targeted at the microenvironment. |
| first_indexed | 2024-03-10T15:03:36Z |
| format | Article |
| id | doaj.art-f61586e189f14192ad4e01c6585c3b96 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T15:03:36Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f61586e189f14192ad4e01c6585c3b962023-11-20T19:58:58ZengMDPI AGPharmaceutics1999-49232020-11-011211105810.3390/pharmaceutics12111058Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial CellsRagnhild Haugse0Anika Langer1Elisa Thodesen Murvold2Daniela Elena Costea3Bjørn Tore Gjertsen4Odd Helge Gilja5Spiros Kotopoulis6Gorka Ruiz de Garibay7Emmet McCormack8Centre for Pharmacy, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayCentre for Cancer Biomarkers CCBIO, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayKinN Therapeutics AS, Jonas Lies vei 91B, 5021 Bergen, NorwayCentre for Cancer Biomarkers CCBIO, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayCentre for Cancer Biomarkers CCBIO, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayDepartment of Clinical Medicine, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayDepartment of Clinical Medicine, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayCentre for Cancer Biomarkers CCBIO, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayCentre for Pharmacy, Department of Clinical Science, The University of Bergen, Jonas Lies vei 65, 5021 Bergen, NorwayThe use of ultrasound (US) and microbubbles (MB), usually referred to as sonoporation, has great potential to increase the efficacy of chemotherapy. However, the molecular mechanisms that mediate sonoporation response are not well-known, and recent research suggests that cell stress induced by US + MBs may contribute to the treatment benefit. Furthermore, there is a growing understanding that the effects of US + MBs are beyond only the cancer cells and involves the tumour vasculature and microenvironment. We treated pancreatic cancer cells (MIA PaCa-2) and stromal cells, fibroblasts (BJ) and human umbilical vein endothelial cells (HUVECs), with US ± MB, and investigated the extent of uptake of cell impermeable dye (calcein, by flow cytometry), viability (cell count, Annexin/PI and WST-1 assays) and activation of a number of key proteins in important intracellular signalling pathways immediately and 2 h after sonoporation (phospho flow cytometry). Different cell types responded differently to US ± MBs in all these aspects. In general, sonoporation induces immediate, transient activation of MAP-kinases (p38, ERK1/2), and an increase in phosphorylation of ribosomal protein S6 together with dephosphorylation of 4E-BP1. The sonoporation stress-response resembles cellular responses to electroporation and pore-forming toxins in membrane repair and restoring cellular homeostasis, and may be exploited therapeutically. The stromal cells were more sensitive to sonoporation than tumoural cells, and further efforts in optimising sonoporation-enhanced therapy should be targeted at the microenvironment.https://www.mdpi.com/1999-4923/12/11/1058sonoporationmicrobubblesultrasoundintracellular signalingphosphorylationultrasound contrast agents |
| spellingShingle | Ragnhild Haugse Anika Langer Elisa Thodesen Murvold Daniela Elena Costea Bjørn Tore Gjertsen Odd Helge Gilja Spiros Kotopoulis Gorka Ruiz de Garibay Emmet McCormack Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells Pharmaceutics sonoporation microbubbles ultrasound intracellular signaling phosphorylation ultrasound contrast agents |
| title | Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells |
| title_full | Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells |
| title_fullStr | Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells |
| title_full_unstemmed | Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells |
| title_short | Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells |
| title_sort | low intensity sonoporation induced intracellular signalling of pancreatic cancer cells fibroblasts and endothelial cells |
| topic | sonoporation microbubbles ultrasound intracellular signaling phosphorylation ultrasound contrast agents |
| url | https://www.mdpi.com/1999-4923/12/11/1058 |
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