p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions
Lactoferrin (LF) is an iron binding glycoprotein of the transferrin family with a wide spectrum of biological effects, including anti-cancer activity. However, the detailed molecular mechanisms of anti-cancer activity of LF have not been fully determined. In this study, we tried to clarify cytotoxic...
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| Format: | Article |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.988335/full |
| _version_ | 1797995433215131648 |
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| author | Maryami Yuliana Kosim Takahiro Fukazawa Mutsumi Miyauchi Nobuyuki Hirohashi Keiji Tanimoto |
| author_facet | Maryami Yuliana Kosim Takahiro Fukazawa Mutsumi Miyauchi Nobuyuki Hirohashi Keiji Tanimoto |
| author_sort | Maryami Yuliana Kosim |
| collection | DOAJ |
| description | Lactoferrin (LF) is an iron binding glycoprotein of the transferrin family with a wide spectrum of biological effects, including anti-cancer activity. However, the detailed molecular mechanisms of anti-cancer activity of LF have not been fully determined. In this study, we tried to clarify cytotoxic functions of LF on various cell lines under hypoxic conditions and elucidate those molecular mechanisms. Cytotoxic activity of LF on cell lines was found to have a range of sensitivities. Hypoxia decreased sensitivity to LF in KD (lip fibroblast) but increased that in HSC2 (oral squamous cell carcinoma). Expression analyses further revealed that LF treatments increased hypoxic HIF-1α, -2α and p53 proteins in KD but attenuated them in HSC2 cells, and decreased HIF-1 target gene, DEC2, in KD but increased it in HSC2, suggesting a possible relationship between LF-modified DEC2 expression and HIF-α protein. MTT assay strikingly demonstrated that cells expressing mutant-type p53 (MT5) were more sensitive to LF than control HepG2 (hepatoma), suggesting an important role of the p53 signal. Knock-down of TP53 (p53 gene) interestingly reduced sensitivity to LF in HepG2, suggesting that p53 may be a target of LF cytotoxic activity. Further analyses with a ferroptosis promoter or inhibitor demonstrated that LF increased ACSL4 in hypoxic MT5, suggesting LF-induced ferroptosis in cells expressing mutant-type p53. In conclusion, hypoxia was found to regulate cytotoxic activities of LF differently among various cell lines, possibly through the p53 signaling pathway. LF further appeared to regulate ferroptosis through a modification of ACSL4 expression. |
| first_indexed | 2024-04-11T10:01:34Z |
| format | Article |
| id | doaj.art-2d61e3fb5b094dd2856fbbbdc1ceeb18 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T10:01:34Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-2d61e3fb5b094dd2856fbbbdc1ceeb182022-12-22T04:30:25ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.988335988335p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditionsMaryami Yuliana Kosim0Takahiro Fukazawa1Mutsumi Miyauchi2Nobuyuki Hirohashi3Keiji Tanimoto4Department of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanNatural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, JapanDepartment of Oral and Maxillofacial Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima , JapanDepartment of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanDepartment of Radiation Disaster Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanLactoferrin (LF) is an iron binding glycoprotein of the transferrin family with a wide spectrum of biological effects, including anti-cancer activity. However, the detailed molecular mechanisms of anti-cancer activity of LF have not been fully determined. In this study, we tried to clarify cytotoxic functions of LF on various cell lines under hypoxic conditions and elucidate those molecular mechanisms. Cytotoxic activity of LF on cell lines was found to have a range of sensitivities. Hypoxia decreased sensitivity to LF in KD (lip fibroblast) but increased that in HSC2 (oral squamous cell carcinoma). Expression analyses further revealed that LF treatments increased hypoxic HIF-1α, -2α and p53 proteins in KD but attenuated them in HSC2 cells, and decreased HIF-1 target gene, DEC2, in KD but increased it in HSC2, suggesting a possible relationship between LF-modified DEC2 expression and HIF-α protein. MTT assay strikingly demonstrated that cells expressing mutant-type p53 (MT5) were more sensitive to LF than control HepG2 (hepatoma), suggesting an important role of the p53 signal. Knock-down of TP53 (p53 gene) interestingly reduced sensitivity to LF in HepG2, suggesting that p53 may be a target of LF cytotoxic activity. Further analyses with a ferroptosis promoter or inhibitor demonstrated that LF increased ACSL4 in hypoxic MT5, suggesting LF-induced ferroptosis in cells expressing mutant-type p53. In conclusion, hypoxia was found to regulate cytotoxic activities of LF differently among various cell lines, possibly through the p53 signaling pathway. LF further appeared to regulate ferroptosis through a modification of ACSL4 expression.https://www.frontiersin.org/articles/10.3389/fphar.2022.988335/fulllactoferrincytotoxic activityhypoxiap53ferroptosis |
| spellingShingle | Maryami Yuliana Kosim Takahiro Fukazawa Mutsumi Miyauchi Nobuyuki Hirohashi Keiji Tanimoto p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions Frontiers in Pharmacology lactoferrin cytotoxic activity hypoxia p53 ferroptosis |
| title | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| title_full | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| title_fullStr | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| title_full_unstemmed | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| title_short | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| title_sort | p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions |
| topic | lactoferrin cytotoxic activity hypoxia p53 ferroptosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.988335/full |
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