Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function.
<h4>Background</h4>Isolated limb perfusion with TNF-α and melphalan is used with remarkable efficiency to treat unresectable limb sarcomas. Here we tested the ability of TNF-α to directly induce apoptosis of sarcoma cells. In addition, we investigated the impact of p53 in the regulation...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2012
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/d7f4a17893274733b648d7cb83c3aa30 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:d7f4a17893274733b648d7cb83c3aa30 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:d7f4a17893274733b648d7cb83c3aa302021-11-18T07:15:17ZAttenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function.1932-620310.1371/journal.pone.0038808https://doaj.org/article/d7f4a17893274733b648d7cb83c3aa302012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22719951/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Isolated limb perfusion with TNF-α and melphalan is used with remarkable efficiency to treat unresectable limb sarcomas. Here we tested the ability of TNF-α to directly induce apoptosis of sarcoma cells. In addition, we investigated the impact of p53 in the regulation of such effect.<h4>Methodology/principal findings</h4>We first analysed the ability of TNF-α to induce apoptosis in freshly isolated tumour cells. For this purpose, sarcoma tumours (n = 8) treated ex vivo with TNF-α were processed for TUNEL staining. It revealed substantial endothelial cell apoptosis and levels of tumour cell apoptosis that varied from low to high. In order to investigate the role of p53 in TNF-α-induced cell death, human sarcoma cell lines (n = 9) with different TP53 and MDM2 status were studied for their sensitivity to TNF-α. TP53(Wt) cell lines were sensitive to TNF-α unless MDM2 was over-expressed. However, TP53(Mut) and TP53(Null) cell lines were resistant. TP53 suppression in TP53(Wt) cell lines abrogated TNF-α sensitivity and TP53 overexpression in TP53(Null) cell lines restored it. The use of small molecules that restore p53 activity, such as CP-31398 or Nutlin-3a, in association with TNF-α, potentiated the cell death of respectively TP53(Mut) and TP53(Wt)/MDM2(Ampl). In particular, CP-31398 was able to induce p53 as well as some of its apoptotic target genes in TP53(Mut) cells. In TP53(Wt)/MDM2(Ampl) cells, Nutlin-3a effects were associated with a decrease of TNF-α-induced NF-κB-DNA binding and correlated with a differential regulation of pro- and anti-apoptotic genes such as TP53BP2, GADD45, TGF-β1 and FAIM.<h4>Conclusion/significance</h4>More effective therapeutic approaches are critically needed for the treatment of unresectable limb sarcomas. Our results show that restoring p53 activity in sarcoma cells correlated with increased sensitivity to TNF-α, suggesting that this strategy may be an important determinant of TNF-α-based sarcomas treatment.Jane MuretMeriem HasmimIzabela StasikAbdelali JalilAude MallavialleArash NanbakhshLudovic LacroixKaty BillotVéronique BaudJérome ThieryPhilippe VielhPhilippe TerrierJoelle WielsLyubomir VassilevAxel LecesneSylvie BonvalotSalem ChouaibPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e38808 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Jane Muret Meriem Hasmim Izabela Stasik Abdelali Jalil Aude Mallavialle Arash Nanbakhsh Ludovic Lacroix Katy Billot Véronique Baud Jérome Thiery Philippe Vielh Philippe Terrier Joelle Wiels Lyubomir Vassilev Axel Lecesne Sylvie Bonvalot Salem Chouaib Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| description |
<h4>Background</h4>Isolated limb perfusion with TNF-α and melphalan is used with remarkable efficiency to treat unresectable limb sarcomas. Here we tested the ability of TNF-α to directly induce apoptosis of sarcoma cells. In addition, we investigated the impact of p53 in the regulation of such effect.<h4>Methodology/principal findings</h4>We first analysed the ability of TNF-α to induce apoptosis in freshly isolated tumour cells. For this purpose, sarcoma tumours (n = 8) treated ex vivo with TNF-α were processed for TUNEL staining. It revealed substantial endothelial cell apoptosis and levels of tumour cell apoptosis that varied from low to high. In order to investigate the role of p53 in TNF-α-induced cell death, human sarcoma cell lines (n = 9) with different TP53 and MDM2 status were studied for their sensitivity to TNF-α. TP53(Wt) cell lines were sensitive to TNF-α unless MDM2 was over-expressed. However, TP53(Mut) and TP53(Null) cell lines were resistant. TP53 suppression in TP53(Wt) cell lines abrogated TNF-α sensitivity and TP53 overexpression in TP53(Null) cell lines restored it. The use of small molecules that restore p53 activity, such as CP-31398 or Nutlin-3a, in association with TNF-α, potentiated the cell death of respectively TP53(Mut) and TP53(Wt)/MDM2(Ampl). In particular, CP-31398 was able to induce p53 as well as some of its apoptotic target genes in TP53(Mut) cells. In TP53(Wt)/MDM2(Ampl) cells, Nutlin-3a effects were associated with a decrease of TNF-α-induced NF-κB-DNA binding and correlated with a differential regulation of pro- and anti-apoptotic genes such as TP53BP2, GADD45, TGF-β1 and FAIM.<h4>Conclusion/significance</h4>More effective therapeutic approaches are critically needed for the treatment of unresectable limb sarcomas. Our results show that restoring p53 activity in sarcoma cells correlated with increased sensitivity to TNF-α, suggesting that this strategy may be an important determinant of TNF-α-based sarcomas treatment. |
| format |
article |
| author |
Jane Muret Meriem Hasmim Izabela Stasik Abdelali Jalil Aude Mallavialle Arash Nanbakhsh Ludovic Lacroix Katy Billot Véronique Baud Jérome Thiery Philippe Vielh Philippe Terrier Joelle Wiels Lyubomir Vassilev Axel Lecesne Sylvie Bonvalot Salem Chouaib |
| author_facet |
Jane Muret Meriem Hasmim Izabela Stasik Abdelali Jalil Aude Mallavialle Arash Nanbakhsh Ludovic Lacroix Katy Billot Véronique Baud Jérome Thiery Philippe Vielh Philippe Terrier Joelle Wiels Lyubomir Vassilev Axel Lecesne Sylvie Bonvalot Salem Chouaib |
| author_sort |
Jane Muret |
| title |
Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| title_short |
Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| title_full |
Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| title_fullStr |
Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| title_full_unstemmed |
Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF-α by restoring p53 function. |
| title_sort |
attenuation of soft-tissue sarcomas resistance to the cytotoxic action of tnf-α by restoring p53 function. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/d7f4a17893274733b648d7cb83c3aa30 |
| work_keys_str_mv |
AT janemuret attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT meriemhasmim attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT izabelastasik attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT abdelalijalil attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT audemallavialle attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT arashnanbakhsh attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT ludoviclacroix attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT katybillot attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT veroniquebaud attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT jeromethiery attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT philippevielh attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT philippeterrier attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT joellewiels attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT lyubomirvassilev attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT axellecesne attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT sylviebonvalot attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function AT salemchouaib attenuationofsofttissuesarcomasresistancetothecytotoxicactionoftnfabyrestoringp53function |
| _version_ |
1718423761241243648 |