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2016 ; 7
(38
): 62386-62410
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Inhibition of insulin-like growth factor II (IGF-II)-dependent cell growth by
multidentate pentamannosyl 6-phosphate-based ligands targeting the mannose
6-phosphate/IGF-II receptor
#MMPMID27694692
Zavorka ME
; Connelly CM
; Grosely R
; MacDonald RG
Oncotarget
2016[Sep]; 7
(38
): 62386-62410
PMID27694692
show ga
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds
M6P-capped ligands and IGF-II at different binding sites within the ectodomain
and mediates ligand internalization and trafficking to the lysosome. Multivalent
M6P-based ligands can cross-bridge the M6P/IGF2R, which increases the rate of
receptor internalization, permitting IGF-II binding as a passenger ligand and
subsequent trafficking to the lysosome, where the IGF-II is degraded. This unique
feature of the receptor may be exploited to design novel therapeutic agents
against IGF-II-dependent cancers that will lead to decreased bioavailable IGF-II
within the tumor microenvironment. We have designed a panel of M6P-based ligands
that bind to the M6P/IGF2R with high affinity in a bivalent manner and cause
decreased cell viability. We present evidence that our ligands bind through the
M6P-binding sites of the receptor and facilitate internalization and degradation
of IGF-II from conditioned medium to mediate this cellular response. To our
knowledge, this is the first panel of synthetic bivalent ligands for the
M6P/IGF2R that can take advantage of the ligand-receptor interactions of the
M6P/IGF2R to provide proof-of-principle evidence for the feasibility of novel
chemotherapeutic agents that decrease IGF-II-dependent growth of cancer cells.