Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells
Abstract Background The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and...
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Cell Division |
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| Online Access: | http://link.springer.com/article/10.1186/s13008-018-0043-3 |
| _version_ | 1830484443001782272 |
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| author | Alicja Sznarkowska Anna Kostecka Anna Kawiak Pilar Acedo Mattia Lion Alberto Inga Joanna Zawacka-Pankau |
| author_facet | Alicja Sznarkowska Anna Kostecka Anna Kawiak Pilar Acedo Mattia Lion Alberto Inga Joanna Zawacka-Pankau |
| author_sort | Alicja Sznarkowska |
| collection | DOAJ |
| description | Abstract Background The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene. Results By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch. Finally, PpIX showed potent antitumor effect and inhibited the growth of xenograft human tumors in mice. Conclusion Our findings may in future contribute to the successful repurposing of PpIX into clinical practice. |
| first_indexed | 2024-12-21T18:08:22Z |
| format | Article |
| id | doaj.art-2565f0ae0365422295256ca0f89c0535 |
| institution | Directory Open Access Journal |
| issn | 1747-1028 |
| language | English |
| last_indexed | 2024-12-21T18:08:22Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Division |
| spelling | doaj.art-2565f0ae0365422295256ca0f89c05352022-12-21T18:54:52ZengBMCCell Division1747-10282018-12-0113111210.1186/s13008-018-0043-3Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cellsAlicja Sznarkowska0Anna Kostecka1Anna Kawiak2Pilar Acedo3Mattia Lion4Alberto Inga5Joanna Zawacka-Pankau6Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of GdanskDepartment of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of GdanskDepartment of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of GdanskDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, BiomedicumCentre for Integrative Biology, CIBIO, University of TrentoCentre for Integrative Biology, CIBIO, University of TrentoDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, BiomedicumAbstract Background The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene. Results By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch. Finally, PpIX showed potent antitumor effect and inhibited the growth of xenograft human tumors in mice. Conclusion Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.http://link.springer.com/article/10.1186/s13008-018-0043-3TAp73Protoporphyrin IXApoptosisYeast-based assayMDM2MDMX |
| spellingShingle | Alicja Sznarkowska Anna Kostecka Anna Kawiak Pilar Acedo Mattia Lion Alberto Inga Joanna Zawacka-Pankau Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells Cell Division TAp73 Protoporphyrin IX Apoptosis Yeast-based assay MDM2 MDMX |
| title | Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells |
| title_full | Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells |
| title_fullStr | Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells |
| title_full_unstemmed | Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells |
| title_short | Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells |
| title_sort | reactivation of tap73 tumor suppressor by protoporphyrin ix a metabolite of aminolevulinic acid induces apoptosis in tp53 deficient cancer cells |
| topic | TAp73 Protoporphyrin IX Apoptosis Yeast-based assay MDM2 MDMX |
| url | http://link.springer.com/article/10.1186/s13008-018-0043-3 |
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