Novel mechanism of IGF-binding protein-3 action on prostate cancer cells: inhibition of proliferation, adhesion, and motility

Abstract

IGF-binding protein-3 (IGFBP-3) is a modulator of the IGF-signaling pathway and was described as an anti-cancer agent in prostate cancer. The molecular mechanisms underlying these effects remained, however, largely undefined. We analyzed the influence of recombinant IGFBP-3 on cell proliferation of PC3, Du145, and LNCaP prostate cancer cells. As expected, IGFBP-3 inhibited IGF-stimulated cell proliferation by blocking IGF-mediated proliferation signals, but we observed an IGF-independent inhibitory effect of IGFBP-3 on prostate cancer cell proliferation in long-term cultures. We further investigated the influence of IGFBP-3 on adhesion, motility, and invasion of prostate cancer cells using adhesion assays, live-cell imaging techniques, and matrigel invasion measurements. There was a clear inhibitory effect of IGFBP-3 on tumor cell adhesion to extracellular matrix components in the presence and absence of IGF, whereas cell-cell adhesion was not affected. The same inhibitory effect of IGFBP-3 was determined on cell motility when realtime cell movements were followed. In addition, IGFBP-3 was able to inhibit tumor cell invasion through matrigel. In summary, we show that IGFBP-3 inhibits proliferation, adhesion, migration, and invasion processes of prostate tumor cells. These newly described mechanisms of IGFBP-3 can be of importance for tumor progression and support a role of IGFBP-3 in therapeutic settings.

STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

“…59 On the contrary, some studies have shown IGFBP-3 significantly reduces the migration of PC3 prostate cancer cells, Ewing's sarcoma cells, and non-small cell lung cancers, further emphasizing the multifunctional roles of IGFBP-3 in different human cancers. 4,35,38 Our results demonstrating IGFBP-3's involvement in GBM tumor cell invasion in vitro are also consistent with the findings of previous studies on malignant melanoma and esophageal squamous cell carcinoma.…”

Comprehensive gene expression microarray analysis of Ets-1 blockade in PC3 prostate cancer cells and correlations with prostate cancer tissues: Insights into genes involved in the metastatic cascade

“…Brief ly, IGFbP3 has been shown to inhibit proliferation, adhesion, migration, and invasion processes of prostate tumor cells (24). Studies that investigated cd40 expression in tissues from patients with prostate cancer have concluded that invasive prostate cancer is a cd40-negative tumor (25).…”

“…Among the genes affected by Ets-1 in Pc3 cells and involved in apoptosis, we analyzed AR, IGFbP3, VAV3, PTH, PRKCE, IFI16, CCL2, DLC1, XAF1 and TLR4 which are known to be involved in prostate cancer (20,24,(28)(29)(30)(31)(32)(33)(34)(35) (Tables III and IV). AR, IFI16, CCL2, DLC1, XAF1 and TLR4 were found to be more than 10-fold down-regulated in Ets-1 blocked Pc3 cells compared to mock control cells, whereas IGFbP3, VAV3, PRkcE, and PTh were shown to be more than a 10-fold up-regulated.…”

“…Genes with an >10-fold up-or down-regulation that may be involved in apoptosis are shown in Tables III and IV. Of these, AR, IGFbP3, VAV3, PTh, PRKCE, IFI16, CCL2, DLC1, UNC5B, GAS2, XAF1 and TLR4 have been reported to be involved in prostate cancer (20,24,(28)(29)(30)(31)(32)(33)(34)(35).…”

Targeting the insulin-like growth factor network in cancer therapy

“…[45][46][47] Furthermore IGFBP3 was described to inhibit cellular adhesion, migration and invasion, as well as enhance the efficacy of radiation-, chemotherapeutic-and pro-apoptotic agents. 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.…”