PRECLINICAL REPORTSArtemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor proteinSteely, Andrea M.; Willoughby, Jamin A. Sr; Sundar, Shyam N.; Aivaliotis, Vasiliki I.; Firestone, Gary L.Author Information Department of Molecular and Cell Biology, Cancer Research Laboratory, University of California at Berkeley, Berkeley, California, USA Correspondence to Gary L. Firestone, Department of Molecular and Cell Biology, Cancer Research Laboratory, University of California at Berkeley, 591 LSA, Berkeley, CA 94720-3200, USA Tel: +1 510 642 8319; fax: +1 510 643 6791; e-mail: email@example.com Received July 18, 2016 Accepted June 29, 2017 Anti-Cancer Drugs: October 2017 - Volume 28 - Issue 9 - p 1018-1031 doi: 10.1097/CAD.0000000000000547 Buy Metrics Abstract Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.