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

Abstract

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.

Expansion of immature, nucleated red blood cells by transient low-dose methotrexate immune tolerance induction in mice

“…The CI-MPR is multi-functional, in that it binds proteins bearing the M6P recognition marker as well as the peptide hormone insulin-like growth factor (IGF)-II (hence it is also called IGF-IIR/CI-MPR) [36]. The IGF2R/ CI-MPR rapidly recycles between the cell surface membrane and intracellular membrane compartments, providing for the rapid uptake of both IGF-II and M6P-linked lysosomal enzymes [39]. Clinical studies infusing GAA to patients have demonstrated that GAA has a plasma elimination half-life of 2-3 h, so GAA was quickly taken up into cells (United Surgical Partners International and European Medicines Agency Summary of Product Characteristics, updated 04/02/2020) and was not present in circulation, similar to animal studies [40].…”

Temporal dynamics of protein complex formation and dissociation during human cytomegalovirus infection

“…However, in line with the understanding that protein localization can affect Tm 34,35 , a subset of known and predicted translocating proteins displayed significant Tm shifts during infection. Among these was the multifunctional receptor IGF2R, a protein involved in intracellular retrograde transport 87 . IGF2R was reported to support the replication of the gamma herpesvirus HHV-8 and the retrovirus HIV-1 88,89 , and our results also establish it as a pro-viral factor during HCMV infection.…”

Insulin-Like Growth Factor 2 in Physiology, Cancer, and Cancer Treatment

“…In virtue of this binding, IGF2 can be internalized by the IGF2R and degraded in the lysosome. These compounds have been found to be successful at reducing cell viability, IGF2 induced proliferation, and survival in vitro [148]. Another channel for reducing IGF2 bioavailability would be to disrupt the imprinting of IGF2 gene in such a way that neither paternal nor maternal IGF2 copy expresses IGF2.…”