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Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy
Author(s) -
Pham Victor,
Rendon Raymond,
Le Vinh X.,
Tippin Matthew,
Fu DongJun,
Le Thanh H.,
Miller Marvin,
Agredano Ericka,
Cedano Jose,
Zi Xiaolin
Publication year - 2020
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23140
Subject(s) - neddylation , nedd8 , biology , autophagy , microbiology and biotechnology , cell culture , atg8 , cancer research , cancer cell , kinase , downregulation and upregulation , prostate cancer , cancer , ubiquitin , biochemistry , apoptosis , genetics , ubiquitin ligase , gene
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 anticancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell‐expressed developmentally downregulated 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. The 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 downregulated and upregulated 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.