Inhibition of Rac1 reverses enzalutamide resistance in castration‑resistant prostate cancer

Chen,Xiaoliang; Yin,Lili; Qiao,Gan; Li,Yanhua; Li,Baoyuan; Bai,Yunfeng; Feng,Feng

doi:10.3892/ol.2020.11823

Inhibition of Rac1 reverses enzalutamide resistance in castration‑resistant prostate cancer

Authors:
- Xiaoliang Chen
- Lili Yin
- Gan Qiao
- Yanhua Li
- Baoyuan Li
- Yunfeng Bai
- Feng Feng
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Affiliations: School of Medicine, Shanxi Datong University, Datong, Shanxi 037009, P.R. China, School of Life Sciences, Shanxi Datong University, Datong, Shanxi 037009, P.R. China, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Chemistry, School of Chemistry and Environmental Engineering, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
Published online on: July 8, 2020 https://doi.org/10.3892/ol.2020.11823
Pages: 2997-3005
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Enzalutamide, an androgen receptor inhibitor, has been clinically approved for the treatment of metastatic castration‑resistant prostate cancer (CRPC) in the United States. However, patients only benefit from enzalutamide for a short period of time as resistance may develop. Therefore, it is vital to develop a novel strategy to overcome enzalutamide resistance. Ras‑related C3 botulinum toxin substrate 1 (Rac1), which is commonly upregulated in human cancer types, has been recognized as a key molecular component in tumorigenesis, invasion and metastasis. However, the role of Rac1 in enzalutamide‑resistance in prostate cancer (PCa) remains unknown. In the present study, Rac1 was demonstrated to be upregulated in enzalutamide‑resistant PCa cells, and Rac1 knockdown inhibited enzalutamide‑resistant cell proliferation and colony formation. Western blotting results indicated that enzalutamide treatment downregulated the expression levels of JNK and activated transcription factor 2, as well as enhanced the Bax/Bcl‑2 ratio and induced cleavage of poly‑ADP ribose polymerase. Moreover, knockdown of Rac1 in MR49F cells significantly inhibited cell migration and invasion via the downregulation of Snail and the upregulation of E‑cadherin. The results of a nude mouse xenograft tumor model using 22RV1 cells demonstrated that enzalutamide inhibited tumor growth after Rac1 knockdown dramatically, compared to vehicle and single treatment groups. Therefore, the present study provided novel evidence that Rac1 may serve a crucial role in enzalutamide resistance, and that targeting Rac1 may be a potential approach for the treatment of CRPC.

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