Flavokawain A induces deNEDDylation and Skp2 degradation leading to inhibition of tumorigenesis and cancer progression in the TRAMP transgenic mouse model.
S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice. Here we have demonstrated that flavokawain A (FKA), a novel chalcone from the kava plant, selectively inhibited the growth of pRb deficient cell lines and resulted in a proteasome-dependent and ubiquitination-mediated Skp2 degradation. Degradation of Skp2 by FKA was found to be involved in a functional Cullin1, but independent of Cdh1 expression. Further studies have demonstrated that FKA docked into the ATP binding pocket of the precursor cell-expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) complex, inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Finally, dietary feeding of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with FKA inhibited the formation of high-grade prostatic intra-epithelial neoplasia lesions (HG-PIN) and prostate adenocarcinomas, reduced the tumor burden and completely abolished distant organ metastasis. Immunohistochemistry studies revealed that dietary FKA feeding resulted in marked anti-proliferative and apoptotic effects via down-regulation of Skp2 and NEDD8 and up-regulation of p27/Kip1 in the prostate of TRAMP mice. Our findings therefore provide evidence that FKA is a promising NEDDylation inhibitor for targeting Skp2 degradation in prostate cancer prevention and treatment.
Departments of Urology, University of California, Irvine, Orange, CA, USA.|Institutes for Cancer Medicine, Sichuan Medical University, Luzhou, Sichuan, China.
Xuesen
X
Li
Departments of Urology, University of California, Irvine, Orange, CA, USA.
Noriko N
NN
Yokoyama
Departments of Urology, University of California, Irvine, Orange, CA, USA.
Saiyang
S
Zhang
Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University, Zhengzhou, Henan, China.
Lina
L
Ding
Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University, Zhengzhou, Henan, China.
Hong-min
HM
Liu
Division of Hematology-Oncology, Medical University of South Carolina, Charleston, SC, USA.
Michael B
MB
Lilly
Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA, USA.
Dan
D
Mercola
Departments of Urology, University of California, Irvine, Orange, CA, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA, USA.|Pharmacology, University of California, Irvine, Orange, CA, USA.
Xiaolin
X
Zi
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D044842:Cullin Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D000075687:NEDD8 Protein; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D059748:Proteolysis; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*
D016588:Anticarcinogenic Agents; C100318:Cullin 1; D044842:Cullin Proteins; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; C491805:Ube1c protein, mouse; D014452:Ubiquitins; C500809:flavokawain A; D002599:Chalcone; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex
NEDDylation; Skp2; TRAMP; kava; prostate cancer