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10.18632/oncotarget.11493

http://scihub22266oqcxt.onion/10.18632/oncotarget.11493
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C5308735!5308735 !27694692
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suck abstract from ncbi


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pmid27694692
      Oncotarget 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.
  • |Animals [MESH]
  • |Antineoplastic Agents/chemistry/*pharmacology [MESH]
  • |Cell Line, Tumor [MESH]
  • |Cell Proliferation/drug effects [MESH]
  • |Cell Survival/drug effects [MESH]
  • |Humans [MESH]
  • |Insulin-Like Growth Factor II/*metabolism [MESH]
  • |Ligands [MESH]
  • |Lysosomes/metabolism [MESH]
  • |Mannosephosphates/chemistry/*pharmacology [MESH]
  • |Mice [MESH]
  • |Molecular Structure [MESH]
  • |Neoplasms/*drug therapy/pathology [MESH]
  • |Protein Multimerization/drug effects [MESH]
  • |Proteolysis/drug effects [MESH]


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