Abstract
We established previously that IGFBP-3 could exert positive or negative effects on cell function depending upon the extracellular matrix composition and by interacting with integrin signaling. To elicit its pro-apoptotic effects IGFBP-3 bound to caveolin-1 and the beta 1 integrin receptor and increased their association culminating in MAPK activation. Disruption of these complexes or blocking the beta 1 integrin receptor reversed these intrinsic actions of IGFBP-3. In this study we have examined the signaling pathway between integrin receptor binding and MAPK activation that mediates the intrinsic, pro-apoptotic actions of IGFBP-3. We found on inhibiting protein kinase A (PKA), Rho associated kinase (ROCK), and ceramide, the accentuating effects of IGFBP-3 on apoptotic triggers were reversed, such that IGFBP-3 then conferred cell survival. We established that IGFBP-3 activated Rho, the upstream regulator of ROCK and that beta1 integrin and PKA were upstream of Rho activation, whereas the involvement of ceramide was downstream. The beta 1 integrin, PKA, Rho, and ceramide were all upstream of MAPK activation. These data highlight key components involved in the pro-apoptotic effects of IGFBP-3 and that inhibiting them leads to a reversal in the action of IGFBP-3.
Highlights
The IGFs are present in the body almost entirely in association with specific binding proteins of which there are a family of six closely related but distinct proteins (IGFBPs 1–6): IGFBP-3 being the major IGF binding protein in human serum
Preliminary data showed that the apoptotic response to C2 was enhanced in the presence of an activator of protein kinase A (PKA), 8-Bromo-cAMP consistent with activation of PKA being involved in the accentuation of C2-induced apoptosis by IGFBP-3
We found no evidence to suggest that the activation of Rho by IGFBP-3 was modulated in the presence of fumonisin B1 but Figures 5A,B indicate that IGFBP-3 can no longer activate p-MAPK in the presence of fumonisin B1, suggesting that ceramide is acting upstream of MAPK in the enhancement of cell death by IGFBP-3, but downstream of Rho
Summary
The IGFs are present in the body almost entirely in association with specific binding proteins of which there are a family of six closely related but distinct proteins (IGFBPs 1–6): IGFBP-3 being the major IGF binding protein in human serum. IGFBP-3 is known to mediate the growth inhibitory effects of a number of different agents including vitamin D3 and TGF-beta (Perks and Holly, 2003) and inhibits cell growth in human breast cancer cells (Oh et al, 1995). There have been many reports that IGFBP-3 can accentuate apoptosis of different cells including prostate (Rajah et al, 1997), breast (Gill et al, 1997), colorectal (Williams et al, 2000), and esophageal (Hollowood et al, 2000) epithelial cells and induce cell death alone in prostate cancer cells (Rajah et al, 1997) but IGFBP-3 can inhibit apoptosis of nonmalignant mammary epithelial cells (McCaig et al, 2002a) and of HUVEC cells (Granata et al, 2004)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
