Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.

Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifu...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rebekka Müller, Kristine Misund, Toril Holien, Siri Bachke, Karin M Gilljam, Thea K Våtsveen, Torstein B Rø, Emanuele Bellacchio, Anders Sundan, Marit Otterlei
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/40105f6515f04da4aa52f22d17571104
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:40105f6515f04da4aa52f22d17571104
record_format	dspace
spelling	oai:doaj.org-article:40105f6515f04da4aa52f22d175711042021-11-18T09:01:47ZTargeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.1932-620310.1371/journal.pone.0070430https://doaj.org/article/40105f6515f04da4aa52f22d175711042013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936203/?tool=EBIhttps://doaj.org/toc/1932-6203Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.Rebekka MüllerKristine MisundToril HolienSiri BachkeKarin M GilljamThea K VåtsveenTorstein B RøEmanuele BellacchioAnders SundanMarit OtterleiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e70430 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rebekka Müller Kristine Misund Toril Holien Siri Bachke Karin M Gilljam Thea K Våtsveen Torstein B Rø Emanuele Bellacchio Anders Sundan Marit Otterlei Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
description	Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.
format	article
author	Rebekka Müller Kristine Misund Toril Holien Siri Bachke Karin M Gilljam Thea K Våtsveen Torstein B Rø Emanuele Bellacchio Anders Sundan Marit Otterlei
author_facet	Rebekka Müller Kristine Misund Toril Holien Siri Bachke Karin M Gilljam Thea K Våtsveen Torstein B Rø Emanuele Bellacchio Anders Sundan Marit Otterlei
author_sort	Rebekka Müller
title	Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
title_short	Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
title_full	Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
title_fullStr	Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
title_full_unstemmed	Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
title_sort	targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/40105f6515f04da4aa52f22d17571104
work_keys_str_mv	AT rebekkamuller targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT kristinemisund targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT torilholien targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT siribachke targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT karinmgilljam targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT theakvatsveen targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT torsteinbrø targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT emanuelebellacchio targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT anderssundan targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells AT maritotterlei targetingproliferatingcellnuclearantigenanditsproteininteractionsinducesapoptosisinmultiplemyelomacells
_version_	1718421016727781376

Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.

Ejemplares similares