Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic a...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-11-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12576 |
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| _version_ | 1846159298086830080 |
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| author | Michael DiPrima Dunrui Wang Alix Tröster Dragan Maric Nekane Terrades‐Garcia Taekyu Ha Hyeongil Kwak David Sanchez‐Martin Denis Kudlinzki Harald Schwalbe Giovanna Tosato |
| author_facet | Michael DiPrima Dunrui Wang Alix Tröster Dragan Maric Nekane Terrades‐Garcia Taekyu Ha Hyeongil Kwak David Sanchez‐Martin Denis Kudlinzki Harald Schwalbe Giovanna Tosato |
| author_sort | Michael DiPrima |
| collection | DOAJ |
| description | Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma. |
| format | Article |
| id | doaj-art-8f5f33f7824b4646a48a5bac962048a5 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2019-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-8f5f33f7824b4646a48a5bac962048a52024-11-23T12:01:00ZengWileyMolecular Oncology1574-78911878-02612019-11-0113112441245910.1002/1878-0261.12576Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinomaMichael DiPrima0Dunrui Wang1Alix Tröster2Dragan Maric3Nekane Terrades‐Garcia4Taekyu Ha5Hyeongil Kwak6David Sanchez‐Martin7Denis Kudlinzki8Harald Schwalbe9Giovanna Tosato10Laboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USALaboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USACenter for Biomolecular Magnetic Resonance Institute for Organic Chemistry and Chemical Biology Johann Wolfgang Goethe‐University Frankfurt am Main GermanyNational Institutes of Neurological Disorders and Stroke National Institutes of Health (NIH) Bethesda MD USAVasculitis Research Unit Department of Autoimmune Diseases Hospital Clinic University of Barcelona SpainLaboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USALaboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USALaboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USACenter for Biomolecular Magnetic Resonance Institute for Organic Chemistry and Chemical Biology Johann Wolfgang Goethe‐University Frankfurt am Main GermanyCenter for Biomolecular Magnetic Resonance Institute for Organic Chemistry and Chemical Biology Johann Wolfgang Goethe‐University Frankfurt am Main GermanyLaboratory of Cellular Oncology Center for Cancer Research (CCR) National Cancer Institute (NCI) Bethesda MD USAAdvanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.https://doi.org/10.1002/1878-0261.12576cell deathcolorectal cancerEph receptorsEphrin ligandtyrosine kinase signaling |
| spellingShingle | Michael DiPrima Dunrui Wang Alix Tröster Dragan Maric Nekane Terrades‐Garcia Taekyu Ha Hyeongil Kwak David Sanchez‐Martin Denis Kudlinzki Harald Schwalbe Giovanna Tosato Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma Molecular Oncology cell death colorectal cancer Eph receptors Ephrin ligand tyrosine kinase signaling |
| title | Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| title_full | Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| title_fullStr | Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| title_full_unstemmed | Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| title_short | Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| title_sort | identification of eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma |
| topic | cell death colorectal cancer Eph receptors Ephrin ligand tyrosine kinase signaling |
| url | https://doi.org/10.1002/1878-0261.12576 |
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