Aberrant upregulation of CDK1 contributes to medroxyprogesterone acetate (MPA) resistance in cancer-associated fibroblasts of the endometrium.

Autor: Omar IS; Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Universiti Malaya Cancer Research Institute, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia., Mat Adenan NA; Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Department of Obstetrics and Gynaecology, Ara Damansara and Subang Jaya Medical Center, Ramsay Sime Darby Health Care, 47500, Subang Jaya, Selangor, Malaysia., Godoy A; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile; Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, United States., Teo IH; Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia., Gunasagran Y; Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia., Chung I; Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia; Universiti Malaya Cancer Research Institute, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia. Electronic address: ivychung@ummc.edu.my.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2022 Nov 05; Vol. 628, pp. 133-140. Date of Electronic Publication: 2022 Sep 01.
DOI: 10.1016/j.bbrc.2022.08.088
Abstrakt: The response to medroxyprogesterone acetate (MPA) decreases as endometrial disease progresses from the benign to malignancy. In a mouse model, progesterone receptor (PR) expression in normal fibroblasts is accountable for the MPA's inhibitory effects in cancer cells. However, it is still unclear, if and how, fibroblasts from human tumors respond to MPA. In this study, three benign-associated fibroblasts (BAFs) and four cancer-associated fibroblasts (CAFs) were isolated from human benign and cancerous endometrial tissues, respectively, to examine MPA activation on PR signaling. PR-B protein expression were heterogeneously expressed in both CAFs and BAFs, despite a lower mRNA expression in the former. In a luciferase reporter assay, MPA treatment stimulated some PR DNA-binding activity in BAFs but not in CAFs. Yet, activation of PR target gene was generally more pronounced in MPA-treated CAFs compared to BAFs. Cyclin-dependent kinase 1 (CDK1) was exclusively upregulated by 10 nM MPA in CAFs (5.1-fold vs. 1.1-fold in BAFs, P < 0.05), leading to a higher CDK1 protein expression. Subsequently in a dose-response study, CAFs showed an average of ∼20% higher cell viability when compared to BAFs, indicative of drug resistance to MPA. MPA resistance was also observed in EC-CAFs co-culture, when MPA-treated cells showed greater tumor spheroid formation than in EC-BAFs co-culture (2-fold, P < 0.01). The increased cell viability observed in CAFs was reversed with mifepristone (RU486), a PR antagonist which suppressed MPA-induced CDK1 expression. This indicates that MPA-induced abnormal upregulation of CDK1 may contribute to the enhanced CAFs cell proliferation, suggesting a new mechanism of MPA resistance within endometrial cancer microenvironment.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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