Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors
Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00994/full |
| _version_ | 1819044904846753792 |
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| author | Sukhbir Kaur Anthony L. Schwartz David G. Jordan David R. Soto-Pantoja Bethany Kuo Abdel G. Elkahloun Lesley Mathews Griner Craig J. Thomas Marc Ferrer Anish Thomas Sai-Wen Tang Vinodh N. Rajapakse Yves Pommier David D. Roberts |
| author_facet | Sukhbir Kaur Anthony L. Schwartz David G. Jordan David R. Soto-Pantoja Bethany Kuo Abdel G. Elkahloun Lesley Mathews Griner Craig J. Thomas Marc Ferrer Anish Thomas Sai-Wen Tang Vinodh N. Rajapakse Yves Pommier David D. Roberts |
| author_sort | Sukhbir Kaur |
| collection | DOAJ |
| description | Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-malignant cells is mediated in part by enhanced autophagy and protection of anabolic metabolism pathways, but differential H2AX activation kinetics suggested that the DNA damage response is also CD47-dependent. A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11). CD47 mRNA expression positively correlated with schlafen-11 mRNA expression in a subset of human cancers but not the corresponding non-malignant tissues. CD47 mRNA expression was also negatively correlated with SLFN11 promoter methylation in some cancers. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells. The CD47 signaling ligand thrombospondin-1 also suppressed schlafen-11 expression in wild type but not CD47-deficient T cells. Re-expressing SLFN11 restored radiosensitivity to a CD47-deficient Jurkat cells. Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region. The ability of histone deacetylase or topoisomerase inhibitors to induce SLFN11 expression in PC3 cells was lost when CD47 was targeted in these cells. Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation. These data identify CD47 as a context-dependent regulator of SLFN11 expression and suggest an approach to improve radiotherapy and chemotherapy responses by combining with CD47-targeted therapeutics. |
| first_indexed | 2024-12-21T10:20:06Z |
| format | Article |
| id | doaj.art-2fe516e69c1b477cb2a7b06b23d68f0a |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T10:20:06Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-2fe516e69c1b477cb2a7b06b23d68f0a2022-12-21T19:07:27ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-10-01910.3389/fonc.2019.00994491831Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase InhibitorsSukhbir Kaur0Anthony L. Schwartz1David G. Jordan2David R. Soto-Pantoja3Bethany Kuo4Abdel G. Elkahloun5Lesley Mathews Griner6Craig J. Thomas7Marc Ferrer8Anish Thomas9Sai-Wen Tang10Vinodh N. Rajapakse11Yves Pommier12David D. Roberts13Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesCancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United StatesDevelopmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesDevelopmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesDevelopmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesDevelopmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesKnockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-malignant cells is mediated in part by enhanced autophagy and protection of anabolic metabolism pathways, but differential H2AX activation kinetics suggested that the DNA damage response is also CD47-dependent. A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11). CD47 mRNA expression positively correlated with schlafen-11 mRNA expression in a subset of human cancers but not the corresponding non-malignant tissues. CD47 mRNA expression was also negatively correlated with SLFN11 promoter methylation in some cancers. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells. The CD47 signaling ligand thrombospondin-1 also suppressed schlafen-11 expression in wild type but not CD47-deficient T cells. Re-expressing SLFN11 restored radiosensitivity to a CD47-deficient Jurkat cells. Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region. The ability of histone deacetylase or topoisomerase inhibitors to induce SLFN11 expression in PC3 cells was lost when CD47 was targeted in these cells. Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation. These data identify CD47 as a context-dependent regulator of SLFN11 expression and suggest an approach to improve radiotherapy and chemotherapy responses by combining with CD47-targeted therapeutics.https://www.frontiersin.org/article/10.3389/fonc.2019.00994/fullradioresistanceepigeneticsCD47thrombospondin-1DNA damage responseschlafen-11 |
| spellingShingle | Sukhbir Kaur Anthony L. Schwartz David G. Jordan David R. Soto-Pantoja Bethany Kuo Abdel G. Elkahloun Lesley Mathews Griner Craig J. Thomas Marc Ferrer Anish Thomas Sai-Wen Tang Vinodh N. Rajapakse Yves Pommier David D. Roberts Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors Frontiers in Oncology radioresistance epigenetics CD47 thrombospondin-1 DNA damage response schlafen-11 |
| title | Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors |
| title_full | Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors |
| title_fullStr | Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors |
| title_full_unstemmed | Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors |
| title_short | Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors |
| title_sort | identification of schlafen 11 as a target of cd47 signaling that regulates sensitivity to ionizing radiation and topoisomerase inhibitors |
| topic | radioresistance epigenetics CD47 thrombospondin-1 DNA damage response schlafen-11 |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.00994/full |
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