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Authors Wang Z, Yu G, Liu Z, Zhu J, Chen C, Liu R, Xu R
Received 19 December 2017
Accepted for publication 27 February 2018
Published 27 April 2018 Volume 2018:10 Pages 887—897
DOI https://doi.org/10.2147/CMAR.S160292
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Justinn Cochran
Peer reviewer comments 2
Editor who approved publication: Dr Leylah Drusbosky
Background: Paeoniflorin, a polyphenolic compound derived from Radix Paeoniae Alba (Paeonia lactiflora ), has exhibited
anticancer activity in various human cancers, including glioblastoma. However,
the mechanisms underlying the effects of this compound have not been fully
elucidated. Toll-like receptor 4 (TLR4) plays an important role in the
regulation of cancer cell proliferation and progression, and high TLR4
expression in glioblastoma specimens is associated with a poor prognosis. The
present study aimed to investigate whether paeoniflorin suppresses glioblastoma
via inhibition of TLR4 expression.
Methods: CCK-8 experiments and clone formation assay were
performed to detect the cell proliferation. Western blotting was used to
analyze protein expression levels. Detection of Triad3A binding with TLR4 was
assessed by the immunoprecipitation. Orthotopic xenograft mouse model was used
to evaluate the effect of paeoniflorin in vivo. MST was used to analyze the
interaction between paeoniflorin and TLR4 protein.
Results: In our study, we found that paeoniflorin effectively
inhibited glioblastoma growth and suppressed TLR4 protein levels, as well its
downstream effectors both in vivo and in vitro. Moreover, when overexpressed
TLR4 in glioblastoma abolished the effects of paeoniflorin on cell
proliferation, migration, and invasion. Furthermore, we found that paeoniflorin
decreased TLR4 protein through ubiquitination proteasome pathway (UPP)-mediated
degradation in glioblastoma cells. Mechanistically, paeoniflorin promoted
Triad3A to conjugate with TLR4, resulting in degradation. In addition, Triad3A -shRNA abolished
paeoniflorin-enhanced UPP-mediated TLR4 degradation. Finally, we found that
paeoniflorin could directly bind with TLR4 protein as assessed by MST assay.
Conclusion: Our study is the first to identify a novel
mechanism for the antitumor activity of paeoniflorin, specifically: it
decreases tumor growth by directly targeting TLR4 and modulating the
TLR4/Triad3A-dependent axis, leading to TLR4 protein degradation and inhibition
of glioblastoma cell progression in vitro and in vivo. Our current findings
indicate that paeoniflorin is a potential glioblastoma therapeutic agent due to
its Triad3A-dependent ubiquitin degradation of TLR4.
Keywords: paeoniflorin,
glioblastoma, TLR4, ubiquitin, Triad3A