Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth
Retinoic acid (RA) has been widely used to protect skin from photo damage and skin carcinomas caused by solar ultraviolet (UV) irradiation, yet the mechanism remains elusive. Here, we report that all-trans retinoic acid (<i>t</i>RA) can directly induce the expression of a newly identifie...
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| Format: | Article |
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MDPI AG
2019-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/12/1847 |
| _version_ | 1797725298199887872 |
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| author | Yadong Song Hongyan Lu Qiong Wang Rong Xiang |
| author_facet | Yadong Song Hongyan Lu Qiong Wang Rong Xiang |
| author_sort | Yadong Song |
| collection | DOAJ |
| description | Retinoic acid (RA) has been widely used to protect skin from photo damage and skin carcinomas caused by solar ultraviolet (UV) irradiation, yet the mechanism remains elusive. Here, we report that all-trans retinoic acid (<i>t</i>RA) can directly induce the expression of a newly identified potent anti-angiogenic factor, seryl tRNA synthetase (SerRS), whose angiostatic role can, however, be inhibited by UV-activated ataxia telangiectasia mutated (ATM) kinase. In both a human epidermal cell line, HaCaT, and a mouse melanoma B16F10 cell line, we found that <i>t</i>RA could activate SerRS transcription through binding with the SerRS promoter. However, UV irradiation induced activation of ATM-phosphorylated SerRS, leading to the inactivation of SerRS as a transcriptional repressor of vascular endothelial growth factor A (VEGFA), which dampened the effect of <i>t</i>RA. When combined with ATM inhibitor KU-55933, <i>t</i>RA showed a greatly enhanced efficiency in inhibiting VEGFA expression and a much better protection of mouse skin from photo damage. Also, we found the combination greatly inhibited tumor angiogenesis and growth in mouse melanoma xenograft in vivo. Taken together, <i>t</i>RA combined with an ATM inhibitor can greatly enhance the anti-angiogenic activity of SerRS under UV irradiation and could be a better strategy in protecting skin from angiogenesis-associated skin damage and melanoma caused by UV radiation. |
| first_indexed | 2024-03-12T10:29:09Z |
| format | Article |
| id | doaj.art-d0979611ce91447795335293a6097a51 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:29:09Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d0979611ce91447795335293a6097a512023-09-02T09:27:32ZengMDPI AGCancers2072-66942019-11-011112184710.3390/cancers11121847cancers11121847Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma GrowthYadong Song0Hongyan Lu1Qiong Wang2Rong Xiang3School of Medicine, Nankai University, Tianjin 300071, ChinaSchool of Medicine, Nankai University, Tianjin 300071, ChinaSchool of Medicine, Nankai University, Tianjin 300071, ChinaSchool of Medicine, Nankai University, Tianjin 300071, ChinaRetinoic acid (RA) has been widely used to protect skin from photo damage and skin carcinomas caused by solar ultraviolet (UV) irradiation, yet the mechanism remains elusive. Here, we report that all-trans retinoic acid (<i>t</i>RA) can directly induce the expression of a newly identified potent anti-angiogenic factor, seryl tRNA synthetase (SerRS), whose angiostatic role can, however, be inhibited by UV-activated ataxia telangiectasia mutated (ATM) kinase. In both a human epidermal cell line, HaCaT, and a mouse melanoma B16F10 cell line, we found that <i>t</i>RA could activate SerRS transcription through binding with the SerRS promoter. However, UV irradiation induced activation of ATM-phosphorylated SerRS, leading to the inactivation of SerRS as a transcriptional repressor of vascular endothelial growth factor A (VEGFA), which dampened the effect of <i>t</i>RA. When combined with ATM inhibitor KU-55933, <i>t</i>RA showed a greatly enhanced efficiency in inhibiting VEGFA expression and a much better protection of mouse skin from photo damage. Also, we found the combination greatly inhibited tumor angiogenesis and growth in mouse melanoma xenograft in vivo. Taken together, <i>t</i>RA combined with an ATM inhibitor can greatly enhance the anti-angiogenic activity of SerRS under UV irradiation and could be a better strategy in protecting skin from angiogenesis-associated skin damage and melanoma caused by UV radiation.https://www.mdpi.com/2072-6694/11/12/1847uvvegfaatmall-trans retinoic acid (<i>t</i>ra)seryl trna synthetase (serrs)ku55933melanomaphotodamage |
| spellingShingle | Yadong Song Hongyan Lu Qiong Wang Rong Xiang Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth Cancers uv vegfa atm all-trans retinoic acid (<i>t</i>ra) seryl trna synthetase (serrs) ku55933 melanoma photodamage |
| title | Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth |
| title_full | Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth |
| title_fullStr | Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth |
| title_full_unstemmed | Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth |
| title_short | Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth |
| title_sort | targeting angiogenesis by blocking the atm serrs vegfa pathway for uv induced skin photodamage and melanoma growth |
| topic | uv vegfa atm all-trans retinoic acid (<i>t</i>ra) seryl trna synthetase (serrs) ku55933 melanoma photodamage |
| url | https://www.mdpi.com/2072-6694/11/12/1847 |
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