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

Omar, Intan Sofia and Adenan, Noor Azmi Mat and Godoy, Alejandro and Teo, Ik Hui and Gunasagran, Yogeeta and Chung, Ivy (2022) Aberrant upregulation of CDK1 contributes to medroxyprogesterone acetate (MPA) resistance in cancer-associated fibroblasts of the endometrium. Biochemical and Biophysical Research Communications, 628. pp. 133-140. ISSN 0006-291X, DOI https://doi.org/10.1016/j.bbrc.2022.08.088.

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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 similar to 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. (C) 2022 Elsevier Inc. All rights reserved.

Item Type: Article
Funders: Malaysian Ministry of Higher Education [FP029-2014B], Universiti Malaya High Impact Research [UM.C/625/HIR/MED/12]
Uncontrolled Keywords: Endometrial cancer; Uterine cancer; Progestin resistance; Progesterone receptor; Stroma
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 06 Sep 2023 07:44
Last Modified: 06 Sep 2023 07:44
URI: http://eprints.um.edu.my/id/eprint/41116

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