Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein

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.

Artemisinin Prevents Glutamate-Induced Neuronal Cell Death Via Akt Pathway Activation

“…Short pretreatment period of artemisinin may be insufficient and does not take effect (Zheng et al, 2016 ). Second, the dose which was used in our study to activate Akt enzymatic activity is much lower than preview study (Steely et al, 2017 ). Third, dihydroartemisinin is the active metabolite of all artemisinin compounds (Zhao et al, 2012 ).…”

Artemisinin Attenuated Hydrogen Peroxide (H2O2)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway

“…It is one of the most effective anti-malarial drug which has saved the lives of millions of malaria patients worldwide [10,11]. In addition to anti-malarial benefits, artemisinin has many other biological and pharmacological properties, including antioxidant, anti-inflammatory, antiviral and anti-tumor effects [12,13,14]. In addition, we have recently shown that artemisinin have neuroprotective potential [15,16,17].…”

Development of Potential Antitumor Agents from the Scaffolds of Plant-Derived Terpenoid Lactones

“…22,23 It selectively induced the ubiquitin-26S proteasome-mediated degradation of androgen receptor (AR) without altering receptor transcript levels in androgen-responsive LNCaP and PC-3 human prostate cancer cells. 24 The ART-induced loss of AR prevented the cell proliferation and ablated total AR transcriptional activity, in which PI3K (phosphoinositide 3kinase)/Akt-1 signaling played an important role. Thus, the potential of AR-targeted prostate cancer chemotherapy was suggested for ART (Figure 2).…”

“…ART prevented Helicobacter pylori -induced gastric carcinogenesis via inhibition of nuclear factor kappa B (NF-κB) signaling . Interestingly, ART was found to enhance significantly the cytolytic activity of natural killer (NK) cells and the antitumor immune response in 4T1 breast cancer cells. , It selectively induced the ubiquitin-26S proteasome-mediated degradation of androgen receptor (AR) without altering receptor transcript levels in androgen-responsive LNCaP and PC-3 human prostate cancer cells . The ART-induced loss of AR prevented the cell proliferation and ablated total AR transcriptional activity, in which PI3K (phosphoinositide 3-kinase)/Akt-1 signaling played an important role.…”