Cell aggregation activates small GTPase Rac1 and induces CD44 cleavage by maintaining lipid raft integrity
Published by Elsevier Inc..
Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and glycosphingolipids and serve as major platforms for signal transduction. Cell detachment from the extracellular matrix (ECM) triggers lipid raft disruption and anoikis, which is a barrier for cancer cells to metastasize. Compared to single circulating tumor cells (CTCs), our recent studies have demonstrated that CD44-mediatd cell aggregation enhances the stemness, survival and metastatic ability of aggregated cells. Here, we investigated whether and how lipid rafts are involved in CD44-mediated cell aggregation. We found that cell detachment, which mimics the condition when tumor cells detach from the ECM to metastasize, induced lipid raft disruption in single cells, but lipid raft integrity was maintained in aggregated cells. We further found that lipid raft integrity in aggregated cells was required for Rac1 activation to prevent anoikis. In addition, CD44 and γ-secretase coexisted at lipid rafts in aggregated cells, which promoted CD44 cleavage and generated CD44 intracellular domain (CD44 ICD) to enhance stemness of aggregated cells. Consequently, lipid raft disruption inhibited Rac1 activation, CD44 ICD generation, and metastasis. Our findings reveal two new pathways regulated by CD44-mediated cell aggregation via maintaining lipid raft integrity. These findings also suggest that targeting cell aggregation-mediated pathways could be a novel therapeutic strategy to prevent CTC cluster-initiated metastasis.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:299 |
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| Enthalten in: |
The Journal of biological chemistry - 299(2023), 12 vom: 02. Dez., Seite 105377 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Dong [VerfasserIn] |
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| Links: |
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| Themen: |
Anoikis |
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| Anmerkungen: |
Date Completed 11.01.2024 Date Revised 17.01.2024 published: Print-Electronic UpdateOf: Res Sq. 2023 Feb 14;:. - PMID 36824757 Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105377 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363589554 |
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| 500 | |a Date Revised 17.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: Res Sq. 2023 Feb 14;:. - PMID 36824757 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and glycosphingolipids and serve as major platforms for signal transduction. Cell detachment from the extracellular matrix (ECM) triggers lipid raft disruption and anoikis, which is a barrier for cancer cells to metastasize. Compared to single circulating tumor cells (CTCs), our recent studies have demonstrated that CD44-mediatd cell aggregation enhances the stemness, survival and metastatic ability of aggregated cells. Here, we investigated whether and how lipid rafts are involved in CD44-mediated cell aggregation. We found that cell detachment, which mimics the condition when tumor cells detach from the ECM to metastasize, induced lipid raft disruption in single cells, but lipid raft integrity was maintained in aggregated cells. We further found that lipid raft integrity in aggregated cells was required for Rac1 activation to prevent anoikis. In addition, CD44 and γ-secretase coexisted at lipid rafts in aggregated cells, which promoted CD44 cleavage and generated CD44 intracellular domain (CD44 ICD) to enhance stemness of aggregated cells. Consequently, lipid raft disruption inhibited Rac1 activation, CD44 ICD generation, and metastasis. Our findings reveal two new pathways regulated by CD44-mediated cell aggregation via maintaining lipid raft integrity. These findings also suggest that targeting cell aggregation-mediated pathways could be a novel therapeutic strategy to prevent CTC cluster-initiated metastasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CD44 ICD | |
| 650 | 4 | |a Rac1 | |
| 650 | 4 | |a anoikis | |
| 650 | 4 | |a breast cancer | |
| 650 | 4 | |a cell aggregation | |
| 650 | 4 | |a circulating tumor cells | |
| 650 | 4 | |a lipid raft | |
| 650 | 4 | |a metastasis | |
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| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a Hyaluronan Receptors |2 NLM | |
| 650 | 7 | |a rac1 GTP-Binding Protein |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 700 | 1 | |a Park, Younhee |e verfasserin |4 aut | |
| 700 | 1 | |a Hemati, Hami |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xia |e verfasserin |4 aut | |
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