Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression
Abstract Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug sho...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29796-2 |
| _version_ | 1797865069679214592 |
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| author | Alexandra-Larisa Condurat Sepideh Aminzadeh-Gohari Mirjana Malnar Nicole Schider Leonie Opitz Ria Thomas Vishal Menon Barbara Kofler Jan Pruszak |
| author_facet | Alexandra-Larisa Condurat Sepideh Aminzadeh-Gohari Mirjana Malnar Nicole Schider Leonie Opitz Ria Thomas Vishal Menon Barbara Kofler Jan Pruszak |
| author_sort | Alexandra-Larisa Condurat |
| collection | DOAJ |
| description | Abstract Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF’s potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN-amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB. |
| first_indexed | 2024-04-09T23:02:06Z |
| format | Article |
| id | doaj.art-be4f03f793154d44b69f2a4c79def987 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T23:02:06Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-be4f03f793154d44b69f2a4c79def9872023-03-22T10:56:17ZengNature PortfolioScientific Reports2045-23222023-03-0113111510.1038/s41598-023-29796-2Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expressionAlexandra-Larisa Condurat0Sepideh Aminzadeh-Gohari1Mirjana Malnar2Nicole Schider3Leonie Opitz4Ria Thomas5Vishal Menon6Barbara Kofler7Jan Pruszak8Emmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of FreiburgResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityInstitute of Anatomy and Cell Biology, Paracelsus Medical UniversityInstitute of Anatomy and Cell Biology, Paracelsus Medical UniversityInstitute of Anatomy and Cell Biology, Paracelsus Medical UniversityEmmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of FreiburgEmmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of FreiburgResearch Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical UniversityEmmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of FreiburgAbstract Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF’s potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN-amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB.https://doi.org/10.1038/s41598-023-29796-2 |
| spellingShingle | Alexandra-Larisa Condurat Sepideh Aminzadeh-Gohari Mirjana Malnar Nicole Schider Leonie Opitz Ria Thomas Vishal Menon Barbara Kofler Jan Pruszak Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression Scientific Reports |
| title | Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression |
| title_full | Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression |
| title_fullStr | Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression |
| title_full_unstemmed | Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression |
| title_short | Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression |
| title_sort | verteporfin induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of yap taz expression |
| url | https://doi.org/10.1038/s41598-023-29796-2 |
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