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

Abstract

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.

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies

“…In this cell line, the activation of autophagy, which also regulated cell cycle arrest, was the mechanism that mediated the anti-proliferative effects of gartanin [320]. Similarly, it was demonstrated that gartanin (6-24 µM) inhibited the growth of prostate cancer cells (22Rv1, PC-3) by triggering autophagy, as shown by the increase in LC3 II punctuate staining and the increase in LC3 II expression [321].…”

“…However, the use of autophagy inhibitors showed the enhancement of gartanin-induced apoptotic cell death [318]. Conversely, different studies reported the induction of autophagy, as a cell death mechanism, mediated by gartanin [319][320][321]. Liu et al demonstrated that gartanin (10-25 µM) induced both apoptosis and autophagy through the inhibition of the mTOR pathway in urinary bladder cancer cells (T24 and RT4) [319].…”

Emerging Roles of SKP2 in Cancer Drug Resistance

“…With inhibition of the neddylation of Cullin1 and Ubc12, flavokawain A (FKA), flavokawain B (FKB), and gartanin induced Skp2 degradation, which inhibited cell growth and induced autophagy in prostate cancer [ 121 , 122 , 123 ]. All-trans retinoic acid (ATRA) induces ubiquitylation and degradation of the F-box protein Skp2 in Cullin1 independent manner.…”

“…A γ-secretase inhibitor, DAPT, selectively depleted CD133 + cells, suppressed activated NOTCH1 and Skp2, induced p27, inhibited ACC growth in vivo, and sensitized CD133 + cells to radiation [ 65 ]. Gartanin docked onto the NEDD8-activating enzyme (NAE) complex, which results in inhibition of neddylation while inducing proteasomal-dependent Skp2 degradation [ 123 ].…”

“…In addition, it has also been reported that a variety of natural compounds, such as curcumin [ 23 , 54 , 134 ], quercetin [ 134 ], lycopene [ 134 ], epigallocatechin-3-gallate [ 135 ], vitamin D3 [ 132 , 136 ], dioscin [ 137 ], gartanin [ 123 ], and flavokawain A [ 35 , 122 , 138 , 139 , 140 ] inhibit the expression of Skp2 and subsequently exert anti-tumor activity.…”