1. Academic Validation
  2. Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7

Non-drug efflux function of ABCC5 promotes enzalutamide resistance in castration-resistant prostate cancer via upregulation of P65/AR-V7

  • Cell Death Discov. 2022 May 3;8(1):241. doi: 10.1038/s41420-022-00951-4.
Haojie Chen  # 1 Jia Luo  # 2 Shaojun Chen 1 Bowen Shi 1 Xiaocui Zheng 3 Haiying Ji 4 Xiaoqian Zhang 3 Yujia Yin 3 Kun Du 5 Jie Ding 6 Yongjiang Yu 7
Affiliations

Affiliations

  • 1 Department of Urology, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200092, P. R. China.
  • 2 Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 3 Department of Obstetrics and Gynecology, Shanghai Jiao Tong University School of Medicine Xinhua Hospital, Shanghai, China.
  • 4 Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.
  • 5 Department of Laboratory Medicine, Shanghai Jiao Tong University School of Medicine Xinhua Hospital, Shanghai, China. [email protected].
  • 6 Department of Urology, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200092, P. R. China. [email protected].
  • 7 Department of Urology, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200092, P. R. China. [email protected].
  • # Contributed equally.
Abstract

Drug resistance is responsible for castration-resistant prostate Cancer (CRPC)-associated mortality. While ATP binding cassette subfamily C member 5 (ABCC5) has been reported to regulate multiple drug resistance, its drug-efflux function may not be the main reason underlying resistance to enzalutamide, an Androgen Receptor Inhibitor. Here, we aimed to determine whether the non-drug efflux function of ABCC5 affects enzalutamide resistance. The ABCC5 expression data in patients with prostate Cancer (PCa) were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus, and their correlation with disease prognosis was analyzed. Immunohistochemical staining was performed on a cohort of 80 patient samples. Proliferation of enzalutamide-resistant 22RV1 and C4-2B cells was investigated using CCK-8, EdU, and colony formation assays. The effect of ABCC5 silencing on enzalutamide resensitization was evaluated in vitro and in vivo. Functional assays indicated that ABCC5 depletion resensitized enzalutamide-resistant cells to inhibit cell growth and impeded xenograft tumor proliferation. Mechanistically, luciferase and ChIP assays confirmed that P65 regulated AR expression and activity by binding to its promoter, while ABCC5-mediated resistance effected by AR-V7 (one of the widely studied AR splicing variants that meditate AR antagonist resistance) upregulation could be reversed by P65 knockdown. Furthermore, activation of the NF-κB pathway reversed the effects of ABCC5 knockdown by extra AR-V7 expression. Thus, ABCC5 might be a novel target for enzalutamide-resistant CRPC treatment.

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