Gartanin, an isoprenylated xanthone from the mangosteen fruit (<i>Garcinia mangostana</i>), is an androgen receptor degradation enhancer

Li, Gongbo; Petiwala, Sakina M.; Yan, Miao; Won, Jong Hoon; Petukhov, Pavel A.; Johnson, Jeremy J.

doi:10.1002/mnfr.201600037

Cited by 29 publications

(24 citation statements)

References 34 publications

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“…The ERS response pathway is key in protein quality control through the UPR and downstream autophagy activation (Figure S1) . Previous studies have shown that riluzole induces ER morphological distress in PCa cells and ERS is involved in AR protein degradation . Indeed, our data show that thapsigargin, a potent ERS inducer, decreased expression of AR and AR target genes (Figures E and 1F).…”

Section: Resultssupporting

confidence: 55%

“…21 Previous studies have shown that riluzole induces ER morphological distress in PCa cells and ERS is involved in AR protein degradation. [17][18][19]26 Indeed, our data show that thapsigargin, a potent ERS inducer, decreased expression of AR and AR target genes ( Figures 1E and 1F). Since reduction of AR target gene expression by thapsigargin was analogous to riluzole's effect, we hypothesized that riluzole may induce ERS.…”

Section: Rna Extraction Cdna Synthesis and Quantitative Real-timementioning

confidence: 65%

“…We show that riluzole degrades AR‐FL, mutant ARs, and AR‐V7 and decreases AR transcriptional activity. Riluzole promotes protein degradation of AR by activating endoplasmic reticulum stress (ERS), a pathway that has recently been implicated in AR protein stability . The unfolded protein response (UPR) downstream of ERS activation is one of the pathways by which proteins are degraded in the cell .…”

Section: Introductionmentioning

confidence: 99%

“…Riluzole promotes protein degradation of AR by activating endoplasmic reticulum stress (ERS), a pathway that has recently been implicated in AR protein stability. [17][18][19][20] The unfolded protein response (UPR) downstream of ERS activation is one of the pathways by which proteins are degraded in the cell. 21,22 Activating transcription factor-6α (ATF6α), inositolrequiring protein-1α (IRE1α), and protein kinase RNA-like ER kinase (PERK) are ER membrane proteins which activate the three signaling arms of ERS and the downstream UPR ( Figure S1).…”

mentioning

confidence: 99%

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Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

et al. 2018

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Background Prostate cancer (PCa) is diagnosed at the highest rate of all non‐cutaneous male cancers in the United States. The androgen‐dependent (AD) transcription factor, androgen receptor (AR), drives PCa—but inhibiting AR or androgen biosynthesis induces remission for only a short time. At which point, patients acquire more aggressive castration‐resistant (CR) disease with re‐activated AR‐dependent signaling. To combat treatment resistance, down‐regulating AR protein expression has been considered as a potential treatment strategy for CR‐PCa. Methods AD‐ and CR‐PCa cell lines were treated with the well‐tolerated FDA‐approved oral medicine, riluzole. Expression of full‐length or wild‐type AR (AR‐FL) and constitutively active AR‐splice variant 7 (AR‐V7) was assessed by immunoblotting. AR‐FL/AR‐V7 activity was measured using qRT‐PCR of AR‐target genes. Cytoplasmic [Ca2+] levels were measured using a fluorescent Ca2+ indicator microplate assay. Markers of the endoplasmic reticulum stress (ERS) pathway and autophagy were assessed by immunoblotting. Direct interaction between AR and selective autophagy receptor p62 was demonstrated by co‐immunoprecipitation. Results We demonstrate that riluzole downregulates AR‐FL, mutant ARs, and AR‐V7 proteins expression by protein degradation through ERS pathway and selective autophagy. Riluzole also significantly inhibited AR transcription activity by decreasing its target genes expression (PSA, TMPRSS2, and KLK2). Conclusions We provide key mechanistic insights by which riluzole exerts its anti‐tumorigenic effects and induces AR protein degradation via ERS pathways. Our findings support the potential utility of riluzole for treatment of PCa.

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Section: Resultssupporting

confidence: 55%

Section: Rna Extraction Cdna Synthesis and Quantitative Real-timementioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

et al. 2018

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“…Several studies revealed the anticancer activities of xanthones derivative from GM [35][36][37][38][39][40][41]. In HL60 cell line, six xanthones (α-, β-, γ-mangostin, mangostinone, garcinone E and 2-isoprenyl-1, 7-dihydroxy-3-methoxy xanthone) possessed the cytotoxic effect by inhibiting cell growth, while the α-mangostin exerted the highest inhibitory activity than others [3].…”

Section: Anti-tumoral Propertiesmentioning

confidence: 99%

Biological properties in relation to health promotion effects of Garcinia mangostana (queen of fruit)

Karim

Tangpong

2018

JHR

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Purpose -For the prevention and cure of disease, patient use various types of chemical and drug agents. Along with their curative effect, almost all drugs have some destructive effects and side-effects. Due to the minimal and/or none of unwanted side-effect, recently, the use of herbal remedy as the drug of choice becomes the preference choice. The mangosteen, Garcinia mangostana, contains various types of polyphenols. It has been used as a traditional medicine from the ancient times till present days. The purpose of this paper is to investigate the biological properties of mangosteen in relation to health promotion effects. Design/methodology/approach -Several research papers from well-known database (such as PubMed, Google scholar, Scopus and Sciencedirect) were reviewed without considering publication-times to understand the biological properties of mangosteen. Findings -Mangosteen and its xanthone exerted diverse biological activities such as anti-oxidant, anti-inflammatory, anti-allergy, anti-bacteria, anti-fungal, anti-malaria, anticancer and anti-diabetes. Originality/value -Based on these studies, mangosteen is beneficial dietary supplement of overall human health.

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Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy

Pham

Rendon

et al. 2019

Molecular Carcinogenesis

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Gartanin, a 4-prenylated xanthone, has been identified from the purple mangosteen fruit as a potent growth inhibitor of various cancer cell lines, including prostate cancer. However, much of Gartanin's anti-cancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell-expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) complex and next to the NEDD8 binding complex, which leads to inhibit NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 NEDDylation in an in vitro assay. S phase kinase-associated protein (Skp2) and F-box and WD-repeat domain-containing 2 (FBXW2), the NEDD8 family members of E3 ubiqutin ligases, were also down-regulated and up-regulated by Gartainin, respectively. Knock-down of NEDD8 expression by short harpin (Sh) RNAs blocked or attenuated these effects of Gartainin. Finally, Gartanin demonstrated its ability to inhibit growth of prostate cancer lines via autophagy initiation. Our data support that Gartanin is a naturally occurring NEDDylation inhibitor and deserves further investigation for prostate cancer prevention and treatment.

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Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer

Abstract: Gartanin is an isoprenylated xanthone that promotes AR degradation with evidence suggesting this process is critically regulated by the unfolded protein response pathway.

Cited by 29 publications

References 34 publications

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

Biological properties in relation to health promotion effects of Garcinia mangostana (queen of fruit)

Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy

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