Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Abstract The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in pa...

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Autores principales:	Karolina Łuczkowska, Katarzyna Ewa Sokolowska, Olga Taryma-Lesniak, Krzysztof Pastuszak, Anna Supernat, Jonas Bybjerg-Grauholm, Lise Lotte Hansen, Edyta Paczkowska, Tomasz K. Wojdacz, Bogusław Machaliński
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f1af3d190e0e46aab864a91cdf1eba2b
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spelling	oai:doaj.org-article:f1af3d190e0e46aab864a91cdf1eba2b2021-12-02T17:02:21ZBortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound10.1038/s41598-021-89128-02045-2322https://doaj.org/article/f1af3d190e0e46aab864a91cdf1eba2b2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89128-0https://doaj.org/toc/2045-2322Abstract The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.Karolina ŁuczkowskaKatarzyna Ewa SokolowskaOlga Taryma-LesniakKrzysztof PastuszakAnna SupernatJonas Bybjerg-GrauholmLise Lotte HansenEdyta PaczkowskaTomasz K. WojdaczBogusław MachalińskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karolina Łuczkowska Katarzyna Ewa Sokolowska Olga Taryma-Lesniak Krzysztof Pastuszak Anna Supernat Jonas Bybjerg-Grauholm Lise Lotte Hansen Edyta Paczkowska Tomasz K. Wojdacz Bogusław Machaliński Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
description	Abstract The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.
format	article
author	Karolina Łuczkowska Katarzyna Ewa Sokolowska Olga Taryma-Lesniak Krzysztof Pastuszak Anna Supernat Jonas Bybjerg-Grauholm Lise Lotte Hansen Edyta Paczkowska Tomasz K. Wojdacz Bogusław Machaliński
author_facet	Karolina Łuczkowska Katarzyna Ewa Sokolowska Olga Taryma-Lesniak Krzysztof Pastuszak Anna Supernat Jonas Bybjerg-Grauholm Lise Lotte Hansen Edyta Paczkowska Tomasz K. Wojdacz Bogusław Machaliński
author_sort	Karolina Łuczkowska
title	Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
title_short	Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
title_full	Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
title_fullStr	Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
title_full_unstemmed	Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
title_sort	bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f1af3d190e0e46aab864a91cdf1eba2b
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Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

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