Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types
Abstract Background Monepantel is an anti‐helminthic drug that also has anti‐cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism‐of‐action is not fully understood, though effects on cell cycle, mTOR sign...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-06-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.6021 |
| _version_ | 1797775551055790080 |
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| author | Tiffany J. Harris Yang Liao Wei Shi Marco Evangelista Bhupinder Pal Hamsa Puthalakath Roger Aston Richard Mollard John M. Mariadason Erinna F. Lee Walter D. Fairlie |
| author_facet | Tiffany J. Harris Yang Liao Wei Shi Marco Evangelista Bhupinder Pal Hamsa Puthalakath Roger Aston Richard Mollard John M. Mariadason Erinna F. Lee Walter D. Fairlie |
| author_sort | Tiffany J. Harris |
| collection | DOAJ |
| description | Abstract Background Monepantel is an anti‐helminthic drug that also has anti‐cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism‐of‐action is not fully understood, though effects on cell cycle, mTOR signalling and autophagy have been implicated. Methods Viability assays were performed on >20 solid cancer cell cells, and apoptosis assays were performed on a subset of these, including 3D cultures. Genetic deletion of BAX/BAK and ATG were used to establish roles of apoptosis and autophagy in killing activity. RNA‐sequencing was performed on four cell lines after monepantel treatment, and differentially regulated genes were confirmed by Western blotting. Results We showed that monepantel has anti‐proliferative activity on a broad range of cancer cell lines. In some, this was associated with induction of apoptosis which was confirmed using a BAX/BAK‐deficient cell line. However, proliferation is still inhibited in these cells following monepantel treatment, indicating cell‐cycle disruption as the major anti‐cancer effect. Previous studies have also indicated autophagic cell death occurs following monepantel treatment. We showed autophagy induction in multiple cell lines; however, deletion of a key autophagy regulator ATG7 had minimal impact on monepantel’s anti‐proliferative activity, suggesting autophagy is associated with, but not required for its anti‐tumour effects. Transcriptomic analysis of four cell lines treated with monepantel revealed downregulation of many genes involved in the cell cycle, and upregulation of genes linked to ATF4‐mediated ER stress responses, especially those involved in amino‐acid metabolism and protein synthesis. Conclusions As these outcomes are all associated with mTOR signalling, cell cycle and autophagy, we now provide a likely triggering mechanism for the anti‐cancer activity of monepantel. |
| first_indexed | 2024-03-12T22:38:19Z |
| format | Article |
| id | doaj.art-4de6c05fb4a64bbe80971501cf5ed780 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-12T22:38:19Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-4de6c05fb4a64bbe80971501cf5ed7802023-07-21T11:20:58ZengWileyCancer Medicine2045-76342023-06-011212135221353710.1002/cam4.6021Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer typesTiffany J. Harris0Yang Liao1Wei Shi2Marco Evangelista3Bhupinder Pal4Hamsa Puthalakath5Roger Aston6Richard Mollard7John M. Mariadason8Erinna F. Lee9Walter D. Fairlie10Olivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaDepartment of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science La Trobe University Bundoora Victoria AustraliaPharmAust Ltd Claremont AustraliaPharmAust Ltd Claremont AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaOlivia Newton‐John Cancer Research Institute Heidelberg Victoria AustraliaAbstract Background Monepantel is an anti‐helminthic drug that also has anti‐cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism‐of‐action is not fully understood, though effects on cell cycle, mTOR signalling and autophagy have been implicated. Methods Viability assays were performed on >20 solid cancer cell cells, and apoptosis assays were performed on a subset of these, including 3D cultures. Genetic deletion of BAX/BAK and ATG were used to establish roles of apoptosis and autophagy in killing activity. RNA‐sequencing was performed on four cell lines after monepantel treatment, and differentially regulated genes were confirmed by Western blotting. Results We showed that monepantel has anti‐proliferative activity on a broad range of cancer cell lines. In some, this was associated with induction of apoptosis which was confirmed using a BAX/BAK‐deficient cell line. However, proliferation is still inhibited in these cells following monepantel treatment, indicating cell‐cycle disruption as the major anti‐cancer effect. Previous studies have also indicated autophagic cell death occurs following monepantel treatment. We showed autophagy induction in multiple cell lines; however, deletion of a key autophagy regulator ATG7 had minimal impact on monepantel’s anti‐proliferative activity, suggesting autophagy is associated with, but not required for its anti‐tumour effects. Transcriptomic analysis of four cell lines treated with monepantel revealed downregulation of many genes involved in the cell cycle, and upregulation of genes linked to ATF4‐mediated ER stress responses, especially those involved in amino‐acid metabolism and protein synthesis. Conclusions As these outcomes are all associated with mTOR signalling, cell cycle and autophagy, we now provide a likely triggering mechanism for the anti‐cancer activity of monepantel.https://doi.org/10.1002/cam4.6021autophagycell cycleER stressmonepantelmTOR |
| spellingShingle | Tiffany J. Harris Yang Liao Wei Shi Marco Evangelista Bhupinder Pal Hamsa Puthalakath Roger Aston Richard Mollard John M. Mariadason Erinna F. Lee Walter D. Fairlie Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types Cancer Medicine autophagy cell cycle ER stress monepantel mTOR |
| title | Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types |
| title_full | Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types |
| title_fullStr | Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types |
| title_full_unstemmed | Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types |
| title_short | Induction of endoplasmic reticulum stress is associated with the anti‐tumor activity of monepantel across cancer types |
| title_sort | induction of endoplasmic reticulum stress is associated with the anti tumor activity of monepantel across cancer types |
| topic | autophagy cell cycle ER stress monepantel mTOR |
| url | https://doi.org/10.1002/cam4.6021 |
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