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Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma
Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survial. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senesc...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265265/ https://www.ncbi.nlm.nih.gov/pubmed/30206313 http://dx.doi.org/10.1038/s41374-018-0117-5 |
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author | Xie, Jia Xu, Xiuhua Yin, Ping Li, Yinuo Guo, Haiyang Kujawa, Stacy Chakravarti, Debabrata Bulun, Serdar Kim, J. Julie Wei, Jian-Jun |
author_facet | Xie, Jia Xu, Xiuhua Yin, Ping Li, Yinuo Guo, Haiyang Kujawa, Stacy Chakravarti, Debabrata Bulun, Serdar Kim, J. Julie Wei, Jian-Jun |
author_sort | Xie, Jia |
collection | PubMed |
description | Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survial. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senscent cells. |
format | Online Article Text |
id | pubmed-6265265 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-62652652019-03-11 Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma Xie, Jia Xu, Xiuhua Yin, Ping Li, Yinuo Guo, Haiyang Kujawa, Stacy Chakravarti, Debabrata Bulun, Serdar Kim, J. Julie Wei, Jian-Jun Lab Invest Article Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survial. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senscent cells. 2018-09-11 2018-12 /pmc/articles/PMC6265265/ /pubmed/30206313 http://dx.doi.org/10.1038/s41374-018-0117-5 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Xie, Jia Xu, Xiuhua Yin, Ping Li, Yinuo Guo, Haiyang Kujawa, Stacy Chakravarti, Debabrata Bulun, Serdar Kim, J. Julie Wei, Jian-Jun Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title | Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title_full | Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title_fullStr | Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title_full_unstemmed | Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title_short | Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
title_sort | application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265265/ https://www.ncbi.nlm.nih.gov/pubmed/30206313 http://dx.doi.org/10.1038/s41374-018-0117-5 |
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