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Mechanical stiffness augments ligand-dependent progesterone receptor B activation via MEK 1/2 and Rho/ROCK-dependent signaling pathways in uterine fibroid cells.
- Source :
-
Fertility & Sterility . Jul2021, Vol. 116 Issue 1, p255-265. 11p. - Publication Year :
- 2021
-
Abstract
- <bold>Objective: </bold>To test whether mechanical substrate stiffness would influence progesterone receptor B (PRB) signaling in fibroid cells. Uterine fibroids feature an excessive extracellular matrix, increased stiffness, and altered mechanical signaling. Fibroid growth is stimulated by progestins and opposed by anti-progestins, but a functional interaction between progesterone action and mechanical signaling has not been evaluated.<bold>Design: </bold>Laboratory studies.<bold>Setting: </bold>Translational science laboratory.<bold>Patient(s)/animal(s): </bold>Human fibroid cell lines and patient-matched fibroid and myometrial cell lines.<bold>Intervention(s): </bold>Progesterone receptor B-dependent reporter assays and messenger RNA quantitation in cells cultured on stiff polystyrene plates (3GPa) or soft silicone plates (930KPa). Pharmacologic inhibitors of extracellular signal-related protein kinase (ERK) kinase 1/2 (MEK 1/2; PD98059), p38 mitogen-activated protein kinase (SB202190), receptor tyrosine kinases (RTKs; nintedanib), RhoA (A13), and Rho-associated coiled-coil kinase (ROCK; Y27632).<bold>Main Outcome Measure(s): </bold>Progesterone-responsive reporter activation.<bold>Result(s): </bold>Fibroid cells exhibited higher PRB-dependent reporter activity with progesterone (P4) in cells cultured on stiff vs. soft plates. Mechanically induced PRB activation with P4 was decreased 62% by PD98059, 78% by nintedanib, 38% by A13, and 50% by Y27632. Overexpression of the Rho-guanine nucleotide exchange factor (Rho-GEF), AKAP13, significantly increased PRB-dependent reporter activity. Collagen 1 messenger RNA levels were higher in fibroid cells grown on stiff vs. soft plates with P4.<bold>Conclusion(s): </bold>Cells cultured on mechanically stiff substrates had enhanced PRB activation via a mechanism that required MEK 1/2 and AKAP13/RhoA/ROCK signaling pathways. These studies provide a framework to explore the mechanisms by which mechanical stiffness affects progesterone receptor activation. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PROGESTERONE receptors
*MITOGEN-activated protein kinases
*NUCLEOTIDE exchange factors
*RHO-associated kinases
*MESSENGER RNA
*PROTEIN kinases
*EPIDERMAL growth factor receptors
*ADAPTOR proteins
*SILICONES
*RESEARCH
*CELL culture
*PLASTICS
*PROGESTERONE
*UTERINE tumors
*PHOSPHOTRANSFERASES
*PROTEIN kinase inhibitors
*RESEARCH methodology
*CELL receptors
*UTERINE fibroids
*MEDICAL cooperation
*EVALUATION research
*CELLULAR signal transduction
*COMPARATIVE studies
*TRANSFERASES
*CELL lines
*EXTRACELLULAR space
*CARRIER proteins
*LIGANDS (Biochemistry)
*PHARMACODYNAMICS
*CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 00150282
- Volume :
- 116
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Fertility & Sterility
- Publication Type :
- Academic Journal
- Accession number :
- 150970474
- Full Text :
- https://doi.org/10.1016/j.fertnstert.2020.12.011