Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma
| Autor: | Jia Xie, Xiuhua Xu, Debabrata Chakravarti, Ping Yin, Stacy A. Kujawa, J. Julie Kim, Jian-Jun Wei, Serdar E. Bulun, Yinuo Li, Haiyang Guo |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
0301 basic medicine Senescence senescence education Antineoplastic Agents Biology Article Pathology and Forensic Medicine Transcriptome 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Stress Physiological In vivo Culture Techniques Spheroids Cellular Humans Senolytic Molecular Biology Protein kinase B Cellular Senescence senolysis Sulfonamides Aniline Compounds spheroid culutre Leiomyoma Cell Biology Middle Aged Cell biology Gene expression profiling 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Uterine Neoplasms gene expression Female Heterocyclic Compounds 3-Ring Ex vivo |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
| ISSN: | 0023-6837 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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