Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis <i>In vitro</i> and <i>In vivo</i>

Liu, Bing-Rong; Lee, Kuk‐Wha; Li, Heju; Ma, Liqun; Lin, George L.; Chandraratna, Roshantha A.S.; Cohen, Pinchas

doi:10.1158/1078-0432.ccr-04-2160

Cited by 43 publications

(33 citation statements)

References 36 publications

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“…The concentration of IGFBP3 used here represents one of the lowest ever shown to have an in vitro effect (15,(36)(37)(38)(39)(40).…”

Section: Igfbp3-expressing Hscs Inhibit Neovascularization By Protectmentioning

confidence: 99%

“…Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-independent effects.…”

mentioning

confidence: 99%

“…Like the other IGFBPs, IGFBP3 has IGF1-independent effects. IGFBP3 expression is increased by hypoxic conditions and enhances angiogenesis in some systems while inhibiting it in others (14,15), thereby demonstrating potentially contradictory effects on the vasculature.…”

mentioning

confidence: 99%

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IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

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We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

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“…The concentration of IGFBP3 used here represents one of the lowest ever shown to have an in vitro effect (15,(36)(37)(38)(39)(40).…”

Section: Igfbp3-expressing Hscs Inhibit Neovascularization By Protectmentioning

confidence: 99%

mentioning

confidence: 99%

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IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

128

106

View full text Add to dashboard Cite

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“…Elevated serum IGFBP-3 is associated with a decreased risk of prostate (5,6) and colorectal (7,8) cancer. Overexpression of IGFBP-3 decreases tumor formation in xenografts of non-small cell lung cancer cells (9) and M12 human prostate cancer cells (10), and combined treatment with IGFBP-3 and a synthetic ligand for the retinoid X receptor (RXR) decreases tumor growth and increases apoptosis in xenografts of LAPC-4 prostate cancer cells (11). IGFBP-3 expression is decreased in tumor samples from patients with hepatocellular and non-small cell lung carcinomas (12,13).…”

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confidence: 99%

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

Bhattacharyya

Pechhold

Shahjee

et al. 2006

Journal of Biological Chemistry

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Insulin-like growth factor binding protein-3 (IGFBP-3), a secreted protein, has the intrinsic ability to induce apoptosis directly without binding insulin-like growth factors. Previous studies suggested that IGFBP-3 must be secreted to exert its biological functions. IGFBP-3 contains a nuclear localization signal (NLS), and exogenous IGFBP-3 is translocated into the nucleus, suggesting that both secretion and nuclear localization may play important roles in IGFBP-3 action. To address these questions, we fused yellow fluorescent protein (YFP) to mature IGFBP-3 lacking its signal peptide so that it would remain intracellular and mutated the C-terminal NLS of IGFBP-3, 228 KGRKR 232 , to MDGEA. Following transfection of PC-3 human prostate cancer cells with these constructs, Western blots indicated that YFP-IGFBP-3 lacking a signal peptide was cell-associated and not present in the extracellular media. Moreover, the fusion protein was not N-glycosylated, indicating that it had not entered the secretory pathway. Confocal imaging showed that intracellular YFP-MDGEA-IGFBP-3 was predominantly cytoplasmic. Transient transfection of nonsecreted YFP-wild-type IGFBP-3 decreased cell viability, as assessed by staining with annexin V followed by flow cytometry. Induction of cell death was caspase-dependent, indicative of apoptosis. Apoptosis also was induced by the nonsecreted NLS mutant (YFP-MD-GEA-IGFBP-3) alone and when the IGF-binding site also had been mutated. These results indicate that IGFBP-3 can induce apoptosis in an IGF-independent manner without being secreted or concentrated in the nucleus.

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“…Furthermore, IGFBP-3 alone or in combination with chemotherapeutic agents exhibits potent antitumor activity in vitro and in vivo (33). Moreover, anticancer effects of several dietary factors, including silibinin (34), green tea (35), grape seed extract (36), and apigenin (37), are associated with elevated IGFBP-3 levels.…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic and Preventive Effect of RRR-α-Vitamin E Succinate on Prostate Cancer via Induction of Insulin-Like Growth Factor Binding Protein-3

Yin

Chen

et al. 2007

Clinical Cancer Research

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Purpose: Insulin-like growth factor binding protein-3 (IGFBP-3) is a well-known antiproliferative and proapoptotic molecule in prostate cancer, suggesting that targeting IGFBP-3 might produce clinical benefits. In prostate cancer cells, RRR-a-vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis, yet the mechanisms remain to be elucidated.We hypothesize that the protective effects of VES in prostate cancer are mediated by IGFBP-3 up-regulation. Using prostate cancer models, the involvement of IGFBP-3 in the anticancer effect of VES was investigated. Experimental Design: IGFBP-3 mRNA and protein were determined by real-time PCR and Western blotting in prostate cancer cells, xenografted tumors of nude mice, and prostate tumors of transgenic adenocarcinoma mouse prostate (TRAMP) mice. The serum levels of IGFBP-3 were assessed by ELISA.The importance of IGFBP-3 inVES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy. Results: We found thatVES induced IGFBP-3 mRNA and protein levels in human prostate cancer cell lines. Knockdown of IGFBP-3 by small interfering RNA attenuated VES-induced IGFBP-3 expression and VES-mediated antiproliferative and proapoptotic functions. Furthermore, administration of VES resulted in a significant therapeutic effect on LNCaP and PC3 xenografts and a preventive effect on tumorigenic progression in the TRAMP model without overt toxicity. Notably, the therapeutic and preventive efficacy of VES correlated with increased accumulation of IGFBP-3 in mouse serum as well as in the xenograft tumors and TRAMP prostate samples. Consequently, reduced proliferation and induced apoptosis were witnessed. Conclusions: VES mediates its therapeutic and preventive effects against prostate cancer at least partially through up-regulating IGFBP-3, which inhibits cell proliferation and promotes cell apoptosis.

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Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Cited by 43 publications

References 36 publications

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus

The Therapeutic and Preventive Effect of RRR-α-Vitamin E Succinate on Prostate Cancer via Induction of Insulin-Like Growth Factor Binding Protein-3

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