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Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small
molecule inhibitors
#MMPMID26474281
Liu YQ
; Wang XL
; Cheng X
; Lu YZ
; Wang GZ
; Li XC
; Zhang J
; Wen ZS
; Huang ZL
; Gao QL
; Yang LN
; Cheng YX
; Tao SC
; Liu J
; Zhou GB
Oncotarget
2015[Oct]; 6
(33
): 34953-67
PMID26474281
show ga
Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and
is able to stabilize the conformation of some ubiquitin E3 ligases. However, the
role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is
lacking. Here we showed that Skp1 was overexpressed in 36/64 (56.3%) of non-small
cell lung cancers, and elevated Skp1 was associated with poor prognosis. By
structure-based high-throughput virtual screening, we found some Skp1-targeting
molecules including a natural compound 6-O-angeloylplenolin (6-OAP). 6-OAP bound
Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and
proteolysis of oncogenic E3 ligases NIPA, Skp2, and ?-TRCP, and accumulation of
their substrates Cyclin B1, P27 and E-Cadherin. 6-OAP induced prometaphase arrest
and exerted potent anti-lung cancer activity in two murine models and showed low
adverse effect. These results indicate that Skp1 is critical to lung cancer
pathogenesis, and Skp1 inhibitor inactivates crucial oncogenic E3 ligases and
exhibits significant therapeutic potentials.
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