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Caffeic acid phenethyl ester suppresses the expression of androgen receptor variant 7 via inhibition of CDK1 and AKT

Cancer Gene Therapy (2024)Cite this article

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Abstract

Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron. Additionally, CAPE decreased protein stability of AR-V7 and enhanced the proteosome-degradation of AR-V7. We observed that CDK1 and AKT regulated the expression and stability of AR-V7 via phosphorylation of Ser81 and Ser213, respectively. CAPE decreased the expression of CDK1 and AKT. Overexpression of CDK1 restored the abundance of AR-V7 in CAPE-treated PCa cells. Overexpression of AR-V7, AKT or CDK1 rescued the proliferation of PCa cells under CAPE treatment. Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors.

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Fig. 1: Effects of CAPE treatment on expression of genes and proteins involved in AR-V7 signaling pathway.
Fig. 2: Distribution of AR-V7 in nucleus of 22Rv1 cells and VCaP cells under treatment of CAPE as determined by immunofluorescence.
Fig. 3: Effects of CAPE treatment on protein expression and phosphorylation of AR-V7, CDK1 and AKT in PCa cells.
Fig. 4: Effects of overexpression of AR-V7, AKT, and CDK1 on proliferation of PCa cells.
Fig. 5: CAPE treatment suppresses tumor growth and protein expression of AR-V7, CDK1, and AKT in 22Rv1 xenograft in nude mice.
Fig. 6: Summary of the molecular mechanisms how CAPE inhibits the expression and downstream signaling of AR-V7 in PCa cells.

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Data supporting this study were included within the article and supporting materials.

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Acknowledgements

We thank Prof. Der-San Chuu for useful suggestions and comments. We thank the Editor and Reviewers for all the useful and important comments and suggestions.

Funding

This research was funded by National Science and Technology Council (MOST 109-2320-B-400-004-MY3; NSTC 111-2811-B-400-029; NSTC 112-2314-B-400-031; NSTC 112-2314-B-037-128; NSTC 112-2320-B-400-008) and National Health Research Institutes (CS-110-PP-03, CS-111-PP-03).

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Authors and Affiliations

  1. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan

    Ying-Yu Kuo, Chieh Huo & Chih-Pin Chuu

  2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chia-Yang Li

  3. Department of Medical Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chia-Yang Li

  4. PhD Program for Aging and Graduate Institute of Basic Medical Science, China Medical University, Taichung City, Taiwan

    Chih-Pin Chuu

  5. Biotechnology Center, National Chung Hsing University, Taichung City, Taiwan

    Chih-Pin Chuu

  6. Department of Life Sciences, National Central University, Taoyuan City, Taiwan

    Chih-Pin Chuu

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All authors designed the study and the experiments approaches. Y-YK and CH performed the assays and animal experiments. Y-YK and C-PC analyzed the results and generated the figures. Y-YK, CH, C-YL and C-PC wrote and prepared the manuscript.

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Correspondence to Chih-Pin Chuu.

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Kuo, YY., Huo, C., Li, CY. et al. Caffeic acid phenethyl ester suppresses the expression of androgen receptor variant 7 via inhibition of CDK1 and AKT. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00753-z

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