In order to treat metastatic castration-resistant prostate cancer (mCRPC), 2 medications that target the androgen receptor axis are Enzalutamide (ENZ) and Abiraterone acetate (AA). But the majority of those getting these therapies will ultimately develop drug resistance, which is brought about by a number of processes, including the activation of AR splice variant 7 (AR-V7). Therefore, for a study, researchers tested the ability of caffeic acid phenethyl ester (CAPE) to inhibit ENZ- or AA-resistant mCRPC cell tumor development and AR-V7 signaling.

The transcriptional activity of AR-V7, its target genes UBE2C and TMPRSS2, and its splicing factors U2AF65, SF2, and HNRNPF decreased dose-dependently by CAPE therapy. Treatment with cyclohexamide and MG132 demonstrated that CAPE decreased AR-V7 stability and elevated AR-V7 tagged for proteasomal degradation. Fluorescence microscopy showed that treatment with CAPE decreased the stability and abundance of AR-V7 via reducing the nuclear accumulation of AR-V7 and phosphorylation of Ser81 and Ser213 on AR-V7. In addition, the two kinases CDK1 and AKT, which phosphorylate Ser81 and Ser213 on AR, were expressed less when CAPE was present.

Under CAPE treatment, the AR-V7 protein level was restored by overexpression of CDK1, AKT, or c-Myc. In addition, the 22Rv1 xenograft tumor development and the expression of AKT, CDK1, and AR-V7 in tumors were both inhibited by CAPE injection. By inhibiting AR-V7, enzalutamide- or abiraterone-resistant CRPC cells are prevented from proliferating when CAPE and ENZ or AA are administered together.

The findings showed that CAPE therapy decreased the amount of AR-V7 expression in CRPC cells and its stability and transcriptional activity. It inhibited the possible emergence of resistance to enzalutamide and abiraterone via suppression of AR-V7. For CRPC that is enzalutamide-resistant or abiraterone-resistant, CAPE may be a viable treatment drug.