Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis
We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA<sub>1/2</sub> receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non...
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/999 |
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| author | Guanmin Meng Melinda Wuest Xiaoyun Tang Jennifer Dufour Todd P.W. McMullen Frank Wuest David Murray David N. Brindley |
| author_facet | Guanmin Meng Melinda Wuest Xiaoyun Tang Jennifer Dufour Todd P.W. McMullen Frank Wuest David Murray David N. Brindley |
| author_sort | Guanmin Meng |
| collection | DOAJ |
| description | We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA<sub>1/2</sub> receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA<sub>1</sub> receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process. |
| first_indexed | 2024-03-10T20:23:19Z |
| format | Article |
| id | doaj.art-899368baf4bc4c049e43e59c3e75c830 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:23:19Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-899368baf4bc4c049e43e59c3e75c8302023-11-19T22:02:44ZengMDPI AGCancers2072-66942020-04-0112499910.3390/cancers12040999Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast FibrosisGuanmin Meng0Melinda Wuest1Xiaoyun Tang2Jennifer Dufour3Todd P.W. McMullen4Frank Wuest5David Murray6David N. Brindley7Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, CanadaCancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, CanadaDepartment of Oncology, Division of Oncologic Imaging, University of Alberta, Edmonton, AB T6G 2R7, CanadaCancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, CanadaCancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, CanadaCancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, CanadaWe recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA<sub>1/2</sub> receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA<sub>1</sub> receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process.https://www.mdpi.com/2072-6694/12/4/999adipocytesadipose tissuechemokinescytokinesbreast cancervasculitis |
| spellingShingle | Guanmin Meng Melinda Wuest Xiaoyun Tang Jennifer Dufour Todd P.W. McMullen Frank Wuest David Murray David N. Brindley Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis Cancers adipocytes adipose tissue chemokines cytokines breast cancer vasculitis |
| title | Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis |
| title_full | Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis |
| title_fullStr | Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis |
| title_full_unstemmed | Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis |
| title_short | Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis |
| title_sort | dexamethasone attenuates x ray induced activation of the autotaxin lysophosphatidate inflammatory cycle in breast tissue and subsequent breast fibrosis |
| topic | adipocytes adipose tissue chemokines cytokines breast cancer vasculitis |
| url | https://www.mdpi.com/2072-6694/12/4/999 |
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