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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Data supporting this study were included within the article and supporting materials.
References
Green SM, Mostaghel EA, Nelson PS. Androgen action and metabolism in prostate cancer. Mol Cell Endocrinol. 2012;360:3–13.
Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45.
Ricke EA, Williams K, Lee YF, Couto S, Wang Y, Hayward SW, et al. Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis. Carcinogenesis. 2012;33:1391–8.
Hellerstedt BA, Pienta KJ. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin. 2002;52:154–79.
Chuu CP, Kokontis JM, Hiipakka RA, Fukuchi J, Lin HP, Lin CY, et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci. 2011;18:63.
Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305–13.
Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.
Sugiura M, Sato H, Okabe A, Fukuyo M, Mano Y, Shinohara KI, et al. Identification of AR-V7 downstream genes commonly targeted by AR/AR-V7 and specifically targeted by AR-V7 in castration resistant prostate cancer. Transl Oncol. 2021;14:100915.
Cato L, de Tribolet-Hardy J, Lee I, Rottenberg JT, Coleman I, Melchers D, et al. ARv7 represses tumor-suppressor genes in castration-resistant prostate cancer. Cancer Cell. 2019;35:401–13.e6.
Rizzo A, Mollica V, Rosellini M, Marchetti A, Ricci AD, Fiorentino M, et al. Exploring the association between metastatic sites and androgen receptor splice variant 7 (AR-V7) in castration-resistant prostate cancer patients: a meta-analysis of prospective clinical trials. Pathol Res Pract. 2021;222:153440.
Li Q, Wang Z, Yi J, Shen H, Yang Z, Yan L, et al. Clinicopathological characteristics of androgen receptor splicing variant 7 (AR-V7) expression in patients with castration resistant prostate cancer: a systematic review and meta-analysis. Transl Oncol. 2021;14:101145.
Kong D, Sethi S, Li Y, Chen W, Sakr WA, Heath E, et al. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate. 2015;75:161–74.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. New Engl J Med. 2014;371:1028–38.
Qu F, Xie W, Nakabayashi M, Zhang H, Jeong SH, Wang X, et al. Association of AR-V7 and prostate-specific antigen RNA levels in blood with efficacy of abiraterone acetate and enzalutamide treatment in men with prostate cancer. Clin Cancer Res. 2017;23:726–34.
Huang WJ, Huang CH, Wu CL, Lin JK, Chen YW, Lin CL, et al. Propolin G, a prenylflavanone, isolated from Taiwanese propolis, induces caspase-dependent apoptosis in brain cancer cells. J Agric Food Chem. 2007;55:7366–76.
Bhimani RS, Troll W, Grunberger D, Frenkel K. Inhibition of oxidative stress in HeLa cells by chemopreventive agents. Cancer Res. 1993;53:4528–33.
Natarajan K, Singh S, Burke TR Jr., Grunberger D, Aggarwal BB. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA. 1996;93:9090–5.
Chuu CP, Lin HP, Ciaccio MF, Kokontis JM, Hause RJ Jr., Hiipakka RA, et al. Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks. Cancer Prev Res. 2012;5:788–97.
Lin HP, Lin CY, Huo C, Hsiao PH, Su LC, Jiang SS, et al. Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1. Oncotarget. 2015;6:6684–707.
Lin HP, Jiang SS, Chuu CP. Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction, and growth inhibition in PC-3 human prostate cancer cells. PLoS ONE. 2012;7:e31286.
Tseng JC, Lin CY, Su LC, Fu HH, Yang SD, Chuu CP. CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling. Oncotarget. 2016;7:38010–24.
Tseng JC, Wang BJ, Wang YP, Kuo YY, Chen JK, Hour TC, et al. Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells. Phytomedicine. 2023;116:154860.
Kuo YY, Huo C, Lin CY, Lin HP, Liu JS, Wang WC, et al. Caffeic acid phenethyl ester suppresses androgen receptor signaling and stability via inhibition of phosphorylation on Ser81 and Ser213. Cell Commun Signal. 2019;17:100.
Tseng JC, Huang SH, Lin CY, Wang BJ, Huang SF, Shen YY, et al. ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis. Cell Death Dis. 2020;11:376.
Lee CH, Ku JY, Ha JM, Bae SS, Lee JZ, Kim CS, et al. Transcript levels of androgen receptor variant 7 and ubiquitin-conjugating enzyme 2C in hormone sensitive prostate cancer and castration-resistant prostate cancer. Prostate. 2017;77:60–71.
Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457–62.
Yu J, Yu J, Rhodes DR, Tomlins SA, Cao X, Chen G, et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 2007;67:10657–63.
Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010;17:443–54.
Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33:3140–50.
Fan L, Zhang F, Xu S, Cui X, Hussain A, Fazli L, et al. Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells. Proc Natl Acad Sci USA. 2018;115:E4584–E4593.
Taneja SS, Ha S, Swenson NK, Huang HY, Lee P, Melamed J, et al. Cell-specific regulation of androgen receptor phosphorylation in vivo. J Biol Chem. 2005;280:40916–24.
Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH, et al. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 2000;60:6841–5.
Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci USA. 2006;103:15969–74.
Hsu FN, Chen MC, Chiang MC, Lin E, Lee YT, Huang PH, et al. Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. J Biol Chem. 2011;286:33141–9.
Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015;5:7654.
Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol. 2017;71:874–82.
Sciarra A, Gentilucci A, Silvestri I, Salciccia S, Cattarino S, Scarpa S, et al. Androgen receptor variant 7 (AR-V7) in sequencing therapeutic agents for castratrion resistant prostate cancer: a critical review. Medicine. 2019;98:e15608.
Luna Velez MV, Verhaegh GW, Smit F, Sedelaar JPM, Schalken JA. Suppression of prostate tumor cell survival by antisense oligonucleotide-mediated inhibition of AR-V7 mRNA synthesis. Oncogene. 2019;38:3696–709.
Mediwala SN, Sun H, Szafran AT, Hartig SM, Sonpavde G, Hayes TG, et al. The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. Prostate. 2013;73:267–77.
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).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41417-024-00753-z