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Recent Patents on Anti-Cancer Drug Discovery

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ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

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Research Article

Knockdown of RhoA Expression Reverts Enzalutamide Resistance via the p38 MAPK Pathway in Castration-resistant Prostate Cancer

Author(s): Xiaoliang Chen*, Lili Yin, Hui Xu, Jie Rong, Miao Feng, Di Jiang and Yunfeng Bai*

Volume 18, Issue 1, 2023

Published on: 06 July, 2022

Page: [92 - 99] Pages: 8

DOI: 10.2174/1574892817666220325151555

Price: $65

Abstract

Background: Enzalutamide has been approved clinically for the treatment of castrationresistant prostate cancer (CRPC) but is limited by the emergence of resistance. RhoA has been shown to play a vital role in carcinogenesis, invasion, and metastasis. However, the role of RhoA in enzalutamide-resistant prostate cancer (PCa) remains unclear.

Objectives: This study investigated the role of RhoA and the associated mechanisms of RhoA depletion in enzalutamide resistance in CRPC.

Methods: Western blotting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and colony formation assays were used to assess protein expression, survival, and proliferation of PCa cells, respectively. Xenograft experiments and hematoxylin and eosin (H&E) staining were used to detect further effects of RhoA on enzalutamide resistance in vivo.

Results: In the present study, the expression of RhoA, ROCK2, p38, p-p38, and AR was upregulated in enzalutamide-resistant PCa cells treated with enzalutamide, and silencing of RhoA or ROCK2 attenuated enzalutamide-resistant cell proliferation and colony formation. Furthermore, the deletion of RhoA dramatically increased the efficacy of enzalutamide in inhibiting 22RV1-derived xenograft tumor growth. Additionally, there was no significant change in ROCK1 expression in C4-2R cells treated with or without enzalutamide. Mechanistically, the knockdown of RhoA expression reverted the resistance to enzalutamide via RhoA/ROCK2/p38 rather than RhoA/ROCK1/p38.

Conclusion: Our results suggested that RhoA is a promising therapeutic target. As the inhibition of RhoA reverted enzalutamide resistance, it may increase its effectiveness in CRPC.

Keywords: Enzalutamide resistance, prostate cancer, CRPC, RhoA, p38 MAPK pathway, xenograft experiments.

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