title: Insulin-like growth factor (IGF) binding protein-3 regulation of IGF-I is altered in an acidic extracellular environment.
abstract: While extracellular acidification within solid tumors is well-documented, how reduced pH impacts regulation of insulin-like growth factor-I (IGF-I) has not been studied extensively. Because IGF-I receptor binding is affected by IGF binding proteins (IGFBPs), we examined how pH impacted IGFBP-3 regulation of IGF-I. IGF-I binding in the absence of IGFBP-3 was diminished at reduced pH. Addition of IGFBP-3 reduced IGF-I cell binding at pH 7.4 but increased surface association at pH 5.8. This increase in IGF-I binding at pH 5.8 corresponded with an increase in IGFBP-3 cell association. This, however, was not due to an increase in affinity of IGFBP-3 for heparin at reduced pH although both heparinase III treatment and heparin addition reduced IGFBP-3 enhancement of IGF-I binding. An increase in IGF-I binding to IGFBP-3, though, was seen at reduced pH using a cell-free assay. We hypothesize that the enhanced binding of IGF-I at pH 5.8 is facilitated by increased association of IGFBP-3 at this pH and that the resulting cell associated IGF-I is IGFBP-3 and not IGF-IR bound. Increased internalization and nuclear association of IGF-I at pH 5.8 in the presence of IGFBP-3 was evident, yet cell proliferation was reduced by IGFBP-3 at both pH 5.8 and 7.4 indicating that IGFBP-3-cell associated IGF-I does not signal the cell to proliferate and that the resulting transfer of bound IGF-I from IGF-IR to IGFBP-3 results in diminished proliferation. Solution binding of IGF-I by IGFBP-3 is one means by which IGF-I-induced proliferation is inhibited. Our work suggests that an alternative pathway exists by which IGF-I and IGFBP-3 both associate with the cell surface and that this association inhibits IGF-I-induced proliferation.
authors.affiliation: Department of Chemical Engineering, Virginia Polytechnic Institute & State University, Blacksburg, Virginia 24061, USA. kforsten@vt.edu
authors.forename: K E
authors.initials: KE
authors.lastname: Forsten
authors.forename: R M
authors.initials: RM
authors.lastname: Akers
authors.forename: J D
authors.initials: JD
authors.lastname: San Antonio
mesh_terms: D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D011133:Polysaccharide-Lyases / Q000494:pharmacology
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D006493:Heparin; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase