Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner
Lactoferrin (LF) is an iron-binding glycoprotein of the transferrin family and has been suggested to have a variety of biological functions, including anticancer activity. However, the effects of LF and its mechanisms in anticancer therapies, especially in radiotherapy against cancer cells under hyp...
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2024-12-01
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| Series: | Antioxidants |
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| author | Daitoku Murakami Takahiro Fukazawa Michihito Kyo Mutsumi Miyauchi Shigehiro Ono Tomonao Aikawa Nobuyuki Hirohashi Keiji Tanimoto |
| author_facet | Daitoku Murakami Takahiro Fukazawa Michihito Kyo Mutsumi Miyauchi Shigehiro Ono Tomonao Aikawa Nobuyuki Hirohashi Keiji Tanimoto |
| author_sort | Daitoku Murakami |
| collection | DOAJ |
| description | Lactoferrin (LF) is an iron-binding glycoprotein of the transferrin family and has been suggested to have a variety of biological functions, including anticancer activity. However, the effects of LF and its mechanisms in anticancer therapies, especially in radiotherapy against cancer cells under hypoxic conditions, are not well-determined. In this study, we focused on the molecular mechanisms of LF functions in cells under hypoxic conditions. High-dose LF treatment showed cytotoxic activity in a variety of cells, including both non-cancer and cancer cells. Interestingly, hypoxic treatment increased the sensitivity to LF in some cancer cells but decreased it in non-cancer cells. LF treatment also altered sensitivity to radiation treatment: LF significantly increased the viability of irradiated KD non-cancer cells under hypoxic conditions but decreased that of HSC2 cancer cells. These effects were only observed when LF was treated within 3 h of irradiation, but not before irradiation. Importantly, knockdown of <i>HIF1A</i> counteracted these effects in both cell lines. Measurements of ROS activity showed that LF decreased ROS production in KD cells but increased it in HSC2 cells, resulting in a decrease in γH2AX foci in KD cells but an increase in HSC2 cells. RNA-seq and gene set enrichment analysis showed that LF treatment regulated gene expression related to the cell cycle, apoptosis, inflammation, and the NRF2 antioxidant signaling pathway. Quantitative RT-PCR confirmed the downregulation of the pro-apoptotic gene <i>ASC</i> in KD cells and the NRF2-regulated genes in HSC2 cells by LF treatment. Knockdown experiments confirmed the role of ASC in irradiated KD cells and NRF2 in irradiated HSC2 cells with LF treatment. In conclusion, lactoferrin was shown to affect radiation treatment by regulating apoptosis and NRF2 signaling in a cell type-specific manner under hypoxic conditions, suggesting its potential application as a protector or sensitizer for radiation therapy. |
| format | Article |
| id | doaj-art-b7782d81685d4bafa84eba98ba1c1cbe |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-b7782d81685d4bafa84eba98ba1c1cbe2025-01-24T13:19:03ZengMDPI AGAntioxidants2076-39212024-12-01141110.3390/antiox14010001Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific MannerDaitoku Murakami0Takahiro Fukazawa1Michihito Kyo2Mutsumi Miyauchi3Shigehiro Ono4Tomonao Aikawa5Nobuyuki Hirohashi6Keiji Tanimoto7Department of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, JapanDivision of Medical Research Support, Advanced Research Support Center, Ehime University, Toon 791-0295, JapanDepartment of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, JapanLactoferrin (LF) is an iron-binding glycoprotein of the transferrin family and has been suggested to have a variety of biological functions, including anticancer activity. However, the effects of LF and its mechanisms in anticancer therapies, especially in radiotherapy against cancer cells under hypoxic conditions, are not well-determined. In this study, we focused on the molecular mechanisms of LF functions in cells under hypoxic conditions. High-dose LF treatment showed cytotoxic activity in a variety of cells, including both non-cancer and cancer cells. Interestingly, hypoxic treatment increased the sensitivity to LF in some cancer cells but decreased it in non-cancer cells. LF treatment also altered sensitivity to radiation treatment: LF significantly increased the viability of irradiated KD non-cancer cells under hypoxic conditions but decreased that of HSC2 cancer cells. These effects were only observed when LF was treated within 3 h of irradiation, but not before irradiation. Importantly, knockdown of <i>HIF1A</i> counteracted these effects in both cell lines. Measurements of ROS activity showed that LF decreased ROS production in KD cells but increased it in HSC2 cells, resulting in a decrease in γH2AX foci in KD cells but an increase in HSC2 cells. RNA-seq and gene set enrichment analysis showed that LF treatment regulated gene expression related to the cell cycle, apoptosis, inflammation, and the NRF2 antioxidant signaling pathway. Quantitative RT-PCR confirmed the downregulation of the pro-apoptotic gene <i>ASC</i> in KD cells and the NRF2-regulated genes in HSC2 cells by LF treatment. Knockdown experiments confirmed the role of ASC in irradiated KD cells and NRF2 in irradiated HSC2 cells with LF treatment. In conclusion, lactoferrin was shown to affect radiation treatment by regulating apoptosis and NRF2 signaling in a cell type-specific manner under hypoxic conditions, suggesting its potential application as a protector or sensitizer for radiation therapy.https://www.mdpi.com/2076-3921/14/1/1lactoferrinhypoxiaradiationreactive oxygen species (ROS) |
| spellingShingle | Daitoku Murakami Takahiro Fukazawa Michihito Kyo Mutsumi Miyauchi Shigehiro Ono Tomonao Aikawa Nobuyuki Hirohashi Keiji Tanimoto Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner Antioxidants lactoferrin hypoxia radiation reactive oxygen species (ROS) |
| title | Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner |
| title_full | Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner |
| title_fullStr | Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner |
| title_full_unstemmed | Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner |
| title_short | Lactoferrin Modulates Radiation Response Under Hypoxic Conditions, Possibly Through the Regulation of ROS Production in a Cell Type-Specific Manner |
| title_sort | lactoferrin modulates radiation response under hypoxic conditions possibly through the regulation of ros production in a cell type specific manner |
| topic | lactoferrin hypoxia radiation reactive oxygen species (ROS) |
| url | https://www.mdpi.com/2076-3921/14/1/1 |
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