The unfolded protein response links ER stress to cancer-associated thrombosis
Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
JCI insight - 8(2023), 19 vom: 31. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Muse, Oluwatoyosi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.10.2023 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.170148 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cancer | |
| 650 | 4 | |a Hematology | |
| 650 | 4 | |a Thrombosis | |
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| 700 | 1 | |a Patell, Rushad |e verfasserin |4 aut | |
| 700 | 1 | |a Peters, Christian G |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Moua |e verfasserin |4 aut | |
| 700 | 1 | |a El-Darzi, Emale |e verfasserin |4 aut | |
| 700 | 1 | |a Schulman, Sol |e verfasserin |4 aut | |
| 700 | 1 | |a Falanga, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Marchetti, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Russo, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Zwicker, Jeffrey I |e verfasserin |4 aut | |
| 700 | 1 | |a Flaumenhaft, Robert |e verfasserin |4 aut | |
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