TY - JOUR
T1 - Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma
AU - Xie, Jia
AU - Xu, Xiuhua
AU - Yin, Ping
AU - Li, Yinuo
AU - Guo, Haiyang
AU - Kujawa, Stacy
AU - Chakravarti, Debabrata
AU - Bulun, Serdar
AU - Kim, J. Julie
AU - Wei, Jian Jun
N1 - Funding Information:
Acknowledgements This study was supported by NIH P01HD57877. This work was also partially supported by the Northwestern University Pathology Core Facility and NUSeq core for the gene profiling studies from a Cancer Center Support Grant (NCI CA060553).
Publisher Copyright:
© 2018, United States & Canadian Academy of Pathology.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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 survival. 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 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 senescent cells.
AB - 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 survival. 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 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 senescent cells.
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U2 - 10.1038/s41374-018-0117-5
DO - 10.1038/s41374-018-0117-5
M3 - Article
C2 - 30206313
AN - SCOPUS:85053506252
SN - 0023-6837
VL - 98
SP - 1575
EP - 1587
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 12
ER -