Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27780915
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Efficacy of glycogen synthase kinase-3? targeting against osteosarcoma via
activation of ?-catenin
#MMPMID27780915
Shimozaki S
; Yamamoto N
; Domoto T
; Nishida H
; Hayashi K
; Kimura H
; Takeuchi A
; Miwa S
; Igarashi K
; Kato T
; Aoki Y
; Higuchi T
; Hirose M
; Hoffman RM
; Minamoto T
; Tsuchiya H
Oncotarget
2016[Nov]; 7
(47
): 77038-77051
PMID27780915
show ga
Development of innovative more effective therapy is required for refractory
osteosarcoma patients. We previously established that glycogen synthase kinase-3?
(GSK- 3?) is a therapeutic target in various cancer types. In the present study,
we explored the therapeutic efficacy of GSK-3? inhibition against osteosarcoma
and the underlying molecular mechanisms in an orthotopic mouse model. Expression
and phosphorylation of GSK-3? in osteosarcoma and normal osteoblast cell lines
was examined, together with efficacy of GSK-3? inhibition on cell survival,
proliferation and apoptosis and on the growth of orthotopically-transplanted
human osteosarcoma in nude mice. We also investigated changes in expression,
phosphorylation and co-transcriptional activity of ?-catenin in osteosarcoma
cells following GSK-3? inhibition. Expression of the active form of GSK- 3?
(tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells.
Inhibition of GSK-3? activity by pharmacological inhibitors or of its expression
by RNA interference suppressed proliferation of osteosarcoma cells and induced
apoptosis. Treatment with GSK-3?-specific inhibitors attenuated the growth of
orthotopic osteosaroma in mice. Inhibition of GSK-3? reduced phosphorylation at
GSK- 3?-phospho-acceptor sites in ?-catenin and increased ?-catenin expression,
nuclear localization and co-transcriptional activity. These results suggest the
efficacy of GSK-3? inhibitors is associated with activation of ?-catenin, a
putative tumor suppressor in bone and soft tissue sarcoma and an important
component of osteogenesis. Our study thereby demonstrates a critical role for
GSK-3? in sustaining survival and proliferation of osteosarcoma cells, and
identifies this kinase as a potential therapeutic target against osteosarcoma.
free
free
free
