pH dependent regulation of IGF-I by IGFBP-3

摘要

Acidification of the local environment is characteristic of most solid tumors (1). This reduction in external pH has been linked to both a reduction in oxygen supply and metabolite removal due to lack of sufficient vascularization (2) and increased activity of the cells themselves (3). Our studies focus on how acidification might impact growth factor binding and activity particularly focusing on the insulinlike growth factor family, based on evidence linking this family with tumorigenicity and neoplastic growth (4). Insulin-like growth factor-I (IGF-I) signals through the IGF-I cell surface receptor (IGF-IR) although its activity can be modulated by IGF binding proteins (ICFBPs). There are six ICFBPs of which several, including IGFBP-3, can associate with the cell surface. IGFBP-3 has a heparin binding domain and has been shown to interact with a number of extracellular matrix molecules including collagen and fibrinogen (5). IGFBP-3 has been shown to both potentiate and inhibit IGF-I activity and enhancement appears to require cellular association (6). Recent studies have indicated that secreted proteases capable of generating IGFBP-3 fragments may have a significant impact on IGFBP-3 activity, both ICF-I dependent and independent (7). Increased protease activity at reduced pH has been suggested as a mechanism for ICFBP-3 regulation in the tumor environment (S). Alternatively, we have examined whether IGFBP-3 activity, in lieu of cellular protease activity may be directly altered by acidic conditions. We have found that cell association, internalization and cellular distribution of IGF-I is altered by the presence of ICFBP-3 and that this regulation may provide an alternative means of inhibiting ICF-I response at reduced local pH.