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Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells
Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cell...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858284/ https://www.ncbi.nlm.nih.gov/pubmed/33155399 http://dx.doi.org/10.1002/1878-0261.12845 |
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author | Dolinschek, Romana Hingerl, Julia Benge, Anke Zafiu, Christian Schüren, Elisabeth Ehmoser, Eva‐Kathrin Lössner, Daniela Reuning, Ute |
author_facet | Dolinschek, Romana Hingerl, Julia Benge, Anke Zafiu, Christian Schüren, Elisabeth Ehmoser, Eva‐Kathrin Lössner, Daniela Reuning, Ute |
author_sort | Dolinschek, Romana |
collection | PubMed |
description | Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high‐affinity and constitutively signaling‐competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D‐hydrogels, involving p27(kip) upregulation. Moreover, it promoted EGF‐R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti‐apoptotic factors Bcl‐2 and survivin suppressing caspase activation, compared to a signaling‐incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3‐dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3‐triggered prosurvival signaling. |
format | Online Article Text |
id | pubmed-7858284 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78582842021-02-05 Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells Dolinschek, Romana Hingerl, Julia Benge, Anke Zafiu, Christian Schüren, Elisabeth Ehmoser, Eva‐Kathrin Lössner, Daniela Reuning, Ute Mol Oncol Research Articles Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high‐affinity and constitutively signaling‐competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D‐hydrogels, involving p27(kip) upregulation. Moreover, it promoted EGF‐R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti‐apoptotic factors Bcl‐2 and survivin suppressing caspase activation, compared to a signaling‐incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3‐dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3‐triggered prosurvival signaling. John Wiley and Sons Inc. 2020-12-01 2021-02 /pmc/articles/PMC7858284/ /pubmed/33155399 http://dx.doi.org/10.1002/1878-0261.12845 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Dolinschek, Romana Hingerl, Julia Benge, Anke Zafiu, Christian Schüren, Elisabeth Ehmoser, Eva‐Kathrin Lössner, Daniela Reuning, Ute Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title | Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title_full | Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title_fullStr | Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title_full_unstemmed | Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title_short | Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
title_sort | constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858284/ https://www.ncbi.nlm.nih.gov/pubmed/33155399 http://dx.doi.org/10.1002/1878-0261.12845 |
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