Bicalutamide-Mediated Inhibition of Androgen Receptor Signaling and Its Effect on the Invasion and Migration of Ovarian Cancer Cells
DOI:
https://doi.org/10.64354/968ny790Keywords:
Bicalutamide; Androgen receptor; Ovarian cancer; Cell invasion; Cell migration; Epithelial-mesenchymal transition; MMP-2; MMP-9; PI3K/AKT; SKOV-3; OVCAR-3Abstract
Ovarian cancer remains one of the deadliest gynecological malignancies, largely because it is often detected at advanced stages when metastatic spread has already occurred. The androgen receptor (AR), which is expressed in a substantial proportion of epithelial ovarian carcinomas, has been implicated in promoting tumor cell proliferation, migration, and invasion. Bicalutamide, a well-established nonsteroidal antiandrogen primarily used in the management of prostate cancer, competitively blocks AR-mediated transcriptional activity. However, its potential role in suppressing ovarian cancer cell metastatic behavior has not been thoroughly explored. In this study, we investigated the effects of bicalutamide on the invasion and migration of SKOV-3 and OVCAR-3 ovarian cancer cell lines. Cells were treated with varying concentrations of bicalutamide (10, 25, and 50 µM) for 24 and 48 hours. Cell viability was assessed using the MTT assay, while migration and invasion were evaluated by wound healing and Matrigel-coated Transwell assays, respectively. Western blot analysis was carried out to determine the expression levels of AR, MMP-2, MMP-9, E-cadherin, N-cadherin, and vimentin. Our findings indicate that bicalutamide significantly reduced cell migration and invasion in a dose- and time-dependent manner. These effects were accompanied by downregulation of MMP-2, MMP-9, N-cadherin, and vimentin, alongside upregulation of E-cadherin, suggesting suppression of epithelial-mesenchymal transition (EMT). Furthermore, bicalutamide attenuated PI3K/AKT phosphorylation downstream of AR signaling. These data collectively suggest that bicalutamide may represent a promising adjunctive therapeutic approach against AR-positive ovarian cancers by limiting their metastatic potential.
References
[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249.
[2] Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69(4):280–304.
[3] Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–953.
[4] Gibson DA, Simitsidellis I, Collins F, Saunders PT. Androgens, oestrogens and endometrium: a fine balance between stimulation and inhibition. J Endocrinol. 2020;246(2):R75–R93.
[5] Kossai M, Leary A, Scoazec JY, Genestie C. Ovarian cancer: a heterogeneous disease. Pathobiology. 2018;85(1–2):41–49.
[6] Cardillo MR, et al. Androgen receptors in ovarian tumors: correlation with oestrogen and progesterone receptors. J Exp Clin Cancer Res. 1998;17(2):231–237.
[7] Kollara A, Brown TJ. The role of the androgen receptor in ovarian cancer carcinogenesis and its clinical implications. Oncotarget. 2017;8(17):29395–29405.
[8] Chung WM, et al. Androgen/androgen receptor signaling in ovarian cancer: molecular regulation and therapeutic potentials. Int J Mol Sci. 2021;22(14):7748.
[9] Ligr M, et al. Expression and function of androgen receptor coactivator p44/Mep50/WDR77 in ovarian cancer. PLoS One. 2011;6(10):e26250.
[10] Zhu H, et al. The role of the androgen receptor in ovarian cancer carcinogenesis and its clinical implications. Oncotarget. 2017;8(17):29395–29405.
[11] Furr BJ, Tucker H. The preclinical development of bicalutamide: pharmacodynamics and mechanism of action. Urology. 1996;47(1A Suppl):13–25.
[12] National Library of Medicine. Bicalutamide. In: LiverTox. Bethesda (MD): NCBI; 2012–. Updated 2023.
[13] Hara T, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63(1):149–153.
[14] Levine D, et al. A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission. Cancer. 2007;110(11):2448–2456.
[15] Vasyliev G, et al. A case report of androgen receptor inhibitor therapy in recurrent high-grade serous ovarian cancer. Oncotarget. 2020;11(44):3961–3966.
[16] Beaufort CM, et al. Ovarian cancer cell lines derived from non-serous carcinomas migrate and invade more aggressively. Sci Rep. 2019;9(1):5515.
[17] Elattar A, et al. Androgen receptor expression is a biological marker for androgen sensitivity in high grade serous epithelial ovarian cancer. Gynecol Oncol. 2012;124(1):142–147.
[18] Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2(2):329–333.
[19] Chen J, et al. ZNF277 regulates ovarian cancer cell proliferation and invasion through inhibition of PTEN. Clin Exp Pharmacol Physiol. 2019;46(6):567–578.
[20] Mahmood T, Yang PC. Western blot: technique, theory, and trouble shooting. N Am J Med Sci. 2012;4(9):429–434.
[21] Salomon-Perzynski A, et al. High-grade serous ovarian cancer: the clone wars. Arch Gynecol Obstet. 2017;295(3):569–576.
[22] Du F, et al. Highly and moderately aggressive mouse ovarian cancer cell lines exhibit differential gene expression. Tumour Biol. 2016;37(8):11147–11162.
[23] Roomi MW, et al. Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. Oncol Rep. 2009;21(5):1323–1333.
[24] Li LY, et al. Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med. 2013;11:132.
[25] Luo L, et al. TPL inhibits the invasion and migration of drug-resistant ovarian cancer by targeting the PI3K/AKT/NF-κB-signaling pathway. Front Oncol. 2021;11:704001.
[26] Vergara D, et al. Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett. 2010;291(1):59–66.
[27] Cheng JC, Auersperg N, Leung PC. TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT. PLoS One. 2012;7(8):e42436.
[28] Zhu ML, Kyprianou N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J. 2010;24(3):769–777.
[29] Shoji K, et al. The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer. 2009;101(1):145–148.
[30] Huang J, et al. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation. Gynecol Oncol. 2006;102(2):226–235.
[31] Ying H, et al. The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 2015;6(28):25520–25532.
[32] Sun NK, et al. Androgen plays a carcinogenic role in EOC via the PI3K/AKT signaling pathway in an AR-dependent manner. Biol Sex Differ. 2021;12(1):16.
[33] Shathasivam P, et al. Increased androgen receptor levels and signaling in ovarian cancer cells by VEPH1. J Steroid Biochem Mol Biol. 2020;196:105498.
[34] Domcke S, et al. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 New Journal of Biology and Medicine
This work is licensed under a Creative Commons Attribution 4.0 International License.
