Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis

Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1–mediated transcriptional events

“…[4][5][6][7][8] It may also have IGF-independent antitumor activities through cell-surface or intracellular protein interaction, its nuclear translocation, or its transcriptional regulation. 7,[9][10][11][12] However, the mechanisms that mediate IGFBP-3's IGF-independent antitumor activity have not been clearly defined.…”

“…In support of this notion, IGFBP-3-mediated antitumor activities have been found to involve angiogenesis suppression in various cancer types. 7,8,45 However, to date, the mechanisms by which IGFBP-3 regulates angiogenesis are not understood.We investigated the mechanisms that mediate IGFBP-3's antiangiogenic activity and found that it regulates the expression of bFGF and PDGF, potent angiogenic factors, in NSCLC, HNSCC, and vascular endothelial cells. Because the Egr-1 transcription factor plays a role in regulating these angiogenic factors' expression by binding to the G/C-rich consensus element in their promoters, we determined effects of IGFBP-3 on Egr-1 expression.…”

“…In support of this notion, IGFBP-3-mediated antitumor activities have been found to involve angiogenesis suppression in various cancer types. 7,8,45 However, to date, the mechanisms by which IGFBP-3 regulates angiogenesis are not understood.…”

“…[4][5][6][7][8] It may also have IGF-independent antitumor activities through cell-surface or intracellular protein interaction, its nuclear translocation, or its transcriptional regulation. 7,[9][10][11][12] However, the mechanisms that mediate IGFBP-3's IGF-independent antitumor activity have not been clearly defined.The 82-kDa phosphoprotein transcription factor early growth response protein 1 (Egr-1), an immediate early gene product, has been implicated in multiple cellular processes, including cell growth, apoptosis, wound healing, and angiogenesis. Mitogenic stimuli, including serum, PDGF, peptide growth factors, and B-Raf, and nonmitogenic stresses, including ␥-irradiation and hypoxia, activate Egr-1 expression through serum response elements (SREs) in the Egr-1 promoter, where serum response factor (SRF) and ternary complex factors form transcriptionally active ternary complexes.…”

Targeting the insulin-like growth factor network in cancer therapy

“…47,48 The results of the in vitro studies were partially reproduced in vivo, where recombinant IGFBP3 reduced tumor size and inhibited vascularization in mouse tumor models. [49][50][51] Although repeatedly proposed, currently no clinical studies investigating the antitumor activity of IGFBPs are registered at the database of clinical trials. 5 In summary, IGFBPs represent an alternative to IGF1R targeting strategies.…”