SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells
Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for no...
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MDPI AG
2022-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/1/177 |
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| author | Antje Güttler Claus Weinholdt Elisabeth Ruff Judith Reidt Elisa Darnstaedt Alicia Wildemann Marina Petrenko Jacqueline Keßler Matthias Kappler Ivo Grosse Dirk Vordermark Matthias Bache |
| author_facet | Antje Güttler Claus Weinholdt Elisabeth Ruff Judith Reidt Elisa Darnstaedt Alicia Wildemann Marina Petrenko Jacqueline Keßler Matthias Kappler Ivo Grosse Dirk Vordermark Matthias Bache |
| author_sort | Antje Güttler |
| collection | DOAJ |
| description | Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (<i>SESN2</i>) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of <i>SESN2</i> enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells. |
| first_indexed | 2024-03-11T10:04:55Z |
| format | Article |
| id | doaj.art-6c5e339c8ce648e2a810bedc26dc0609 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T10:04:55Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6c5e339c8ce648e2a810bedc26dc06092023-11-16T15:07:08ZengMDPI AGCells2073-44092022-12-0112117710.3390/cells12010177SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer CellsAntje Güttler0Claus Weinholdt1Elisabeth Ruff2Judith Reidt3Elisa Darnstaedt4Alicia Wildemann5Marina Petrenko6Jacqueline Keßler7Matthias Kappler8Ivo Grosse9Dirk Vordermark10Matthias Bache11Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyInstitute of Computer Science, Martin Luther University Halle-Wittenberg, Von-Seckendorff-Platz 1, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyInstitute of Computer Science, Martin Luther University Halle-Wittenberg, Von-Seckendorff-Platz 1, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyDepartment of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, GermanyBetulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (<i>SESN2</i>) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of <i>SESN2</i> enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells.https://www.mdpi.com/2073-4409/12/1/177betulinic acidsestrin-2knockdownradiosensitivityautophagybreast cancer |
| spellingShingle | Antje Güttler Claus Weinholdt Elisabeth Ruff Judith Reidt Elisa Darnstaedt Alicia Wildemann Marina Petrenko Jacqueline Keßler Matthias Kappler Ivo Grosse Dirk Vordermark Matthias Bache SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells Cells betulinic acid sestrin-2 knockdown radiosensitivity autophagy breast cancer |
| title | SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells |
| title_full | SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells |
| title_fullStr | SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells |
| title_full_unstemmed | SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells |
| title_short | SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells |
| title_sort | sesn2 knockdown increases betulinic acid induced radiosensitivity of hypoxic breast cancer cells |
| topic | betulinic acid sestrin-2 knockdown radiosensitivity autophagy breast cancer |
| url | https://www.mdpi.com/2073-4409/12/1/177 |
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