Omar, Intan Sofia and Abd Jamil, Amira Hajirah and Adenan, Noor Azmi Mat and Chung, Ivy and Chung, Ivy (2022) MPA alters metabolic phenotype of endometrial cancer-associated fibroblasts from obese women via IRS2 signaling. PLoS ONE, 17 (7). ISSN 1932-6203, DOI https://doi.org/10.1371/journal.pone.0270830.
Full text not available from this repository.Abstract
Obese women have a higher risk of developing endometrial cancer (EC) than lean women. Besides affecting EC progression, obesity also affects sensitivity of patients to treatment including medroxprogesterone acetate (MPA). Obese women have a lower response to MPA with an increased risk for tumor recurrence. While MPA inhibits the growth of normal fibroblasts, human endometrial cancer-associated fibroblasts (CAFs) were reported to be less responsive to MPA. However, it is still unknown how CAFs from obese women respond to progesterone. CAFs from the EC tissues of obese (CO) and non-obese (CN) women were established as primary cell models. MPA increased cell proliferation and downregulated stromal differentiation genes, including BMP2 in CO than in CN. Induction of IRS2 (a BMP2 regulator) mRNA expression by MPA led to activation of glucose metabolism in CO, with evidence of greater mRNA levels of GLUT6, GAPDH, PKM2, LDHA, and increased in GAPDH enzymatic activity. Concomitantly, MPA increased the mRNA expression of a fatty acid transporter, CD36 and lipid droplet formation in CO. MPA-mediated increase in glucose metabolism genes in CO was reversed with a progesterone receptor inhibitor, mifepristone (RU486), leading to a decreased proliferation. Our data suggests that PR signaling is aberrantly activated by MPA in CAFs isolated from endometrial tissues of obese women, leading to activation of IRS2 and glucose metabolism, which may lead to lower response and sensitivity to progesterone in obese women.
| Item Type: | Article |
|---|---|
| Funders: | Malaysian Ministry of Higher Education through Fundamental Research Grant Scheme (FRGS) [FP029-2014B], University of Malaya High Impact Research Grant [UM.C/625/HIR/MED/12] |
| Uncontrolled Keywords: | Body-mass index; Medroxyprogesterone acetate; Progesterone-receptor |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 28 Aug 2023 03:58 |
| Last Modified: | 28 Aug 2023 03:58 |
| URI: | http://eprints.um.edu.my/id/eprint/40952 |
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