Insulin-like growth factor-binding protein-3 suppresses tumor growth via activation of caspase-dependent apoptosis and cross-talk with NF-κB signaling
| Autor: | Sherryline Jogie-Brahim, Aki Harada, Youngman Oh, Jinfeng Han |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research medicine.medical_treatment Blotting Western Apoptosis IκB kinase Biology medicine.disease_cause Polymerase Chain Reaction Insulin-like growth factor Prostate cancer Mice Cell Line Tumor medicine Animals Humans RNA Processing Post-Transcriptional DNA Primers Base Sequence Reverse Transcriptase Polymerase Chain Reaction NF-kappa B Cancer Prostatic Neoplasms medicine.disease Molecular biology Immunohistochemistry Enzyme Activation Insulin-Like Growth Factor Binding Proteins Insulin-Like Growth Factor Binding Protein 3 Oncology Tumor progression Caspases Cancer research Tumor necrosis factor alpha Signal transduction Carcinogenesis Cell Division Signal Transduction |
| Zdroj: | Cancer letters. 307(2) |
| ISSN: | 1872-7980 |
| Popis: | Nuclear factor-kappaB (NF-κB) is constitutively activated in a variety of human cancers including prostate cancer and involved in tumorigenesis, tumor progression and chemo-resistance. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a potent tumor suppressor and is significantly suppressed in a variety of cancers. Diverse biological effects of IGFBP-3 have been reported to be both dependent and independent of the IGF/IGF-I receptor (IGF-IR) axis. The precise underlying mechanisms of IGF/IGF-IR-independent, antiproliferative actions of IGFBP-3 are yet to be elucidated. We found an inverse correlation between NF-κB activity and IGFBP-3 expression during prostate cancer progression using an in vitro prostate cancer progression model. Restoration of IGFBP-3 resulted in significant inhibition of constitutively elevated NF-κB activity in prostate cancer cells. IGFBP-3 further inhibited the expression of NF-κB-regulated angiogenic factors such as VEGF and IL-8, and cell adhesion molecules, ICAM-1 and VCAM-1. This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect. We identified that IGFBP-3 degrades the key NF-κB regulatory molecules-IκBα and p65-NF-κB proteins through activation of caspase-8 and -3/-7, thereby inhibiting elevated NF-κB activity in prostate cancer. Finally intratumoral administration of IGFBP-3 resulted in significant tumor suppression as well as sensitization of antitumor effect of doxorubicin. Our findings indicate that IGFBP-3 exerts antitumor effects via IGF-independent mechanisms which involve activation of caspase-dependent apoptosis and cross-talk with NF-κB signaling. The use of IGFBP-3 as a cancer therapeutic with this distinctive suppression mechanism may offer alternate means to treat chemotherapy resistant tumors. |
| Databáze: | OpenAIRE |
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