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Activation of Various Downstream Signaling Molecules by IGFBP-3

Journal of Cancer Therapy 2014年第9期5卷 830-835页

作者： hanief mohammad shahjee Nisan Bhattacharyya Diabetes Branch NIDDK National Institutes of Health Bethesda USA

Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression in cancerous cells but has been known to be present in significant amounts in normal or non-cancerous cells. IGFBP-3 can induce apoptosis in prostate cancer cells either in an IGF-dependent manner or independently of IGF binding. Although putative cell death specific Insulin-like growth factor binding protein-3 (IGFBP-3R) receptor(s) has recently been identified by which IGFBP-3 may induce its anti-tumor effects, IGFBP-3 has also been known to activate various downstream intracellular signaling molecules via a different mechanistic pathway. Stat-1 has been known to be one of the candidate molecules activated by IGFBP-3. IGFBP-3 can also inhibit Akt/IGF-1 survival pathway in MCF-7 breast cancer cells which ultimately leads to the induction of apoptosis in these cells. All these studies clearly demonstrate that IGFBP-3 regulates cell proliferation and promotes its pro-apoptotic effects in cancer cells in two different pathways: 1) sequester IGF-I to bind to IGF-I receptor to inhibit cell proliferation and induce apoptosis, 2) independent of IGF-I pathway, IGFBP-3 binds to some putative receptor and activate various downstream pro-apoptotic molecules involved in cell death.

关键词： Apoptosis IGFBP-3 Stat-1 IGF-I TGF-β

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Signal Transduction Pathways Mediated by Secreted and Non-Secreted Forms of Intact Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) and Its 1-97 N-Terminal Fragment in PC-3 Human Prostate Cancer Cells

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Journal of Cancer Therapy 2013年第8期4卷 1290-1297页

作者： hanief mohammad shahjee Benjamin Kefas Nisan Bhattacharyya Mohamed K. Radwan Department of Biochemistry and Biophysics University of Rochester Medical Center Rochester USA Diabetes Branch NIDDK National Institutes of Health Bethesda USA Division of Neuro-Oncology Neurology Department University of Virginia Health System Charlottesville USA

Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and independent manner. This study was undertaken to delineate possible down-stream signaling pathways that are involved in this process. Intact IGFBP-3 and its N-terminal 1-97 fragments with or without a signal propeptide were fused to YFP and expressed in PC-3 human prostate cancer cells. In some cases, the putative IGF-binding site was presented in full length IGFBP-3 and its N-terminal fragment was also mutated. Extent of apoptosis was quantified using FACS. Up-regulation of total Stat-1 and activation of phospho-Stat-1 were shown by western blot. TGF-β signal was measured by luciferase reporter assay. Results from inhibitor studies indicated that both the Caspase 8 and caspase 9 pathways are involved in IGFBP-3 (non-secreted form) which induced apoptosis in PC-3 cells. Exogenous addition of IGFBP-3 to PC-3 cells increased Stat-1 protein expression/tyrosine phosphorylation. Interestingly, results also showed that knockdown of Stat-1 by siRNA potentiated the IGFBP-3 induced apoptosis in PC-3 cells. In addition, both full-length IGFBP-3 and its 1-97 Nterminal fragments inhibited TGF-β signaling in these cells. This is the first report that compares the signal transduction pathways involved in apoptotic pathways mediated by IGFBP-3 in PC-3 human prostate cancer cells. Non-secreted form of full length IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9. Although, only non-secreted form of IGFBP-3 is involved in inducing apoptosis in PC-3 cells via caspase 8 and caspase 9 activation pathways but both secreted and non-secreted forms of IGFBP-3 are involved in modulating Stat-1 and TGF-β pathways to induce apoptotic actions in PC-3 cells. Non-secreted intact IGFBP-3 and its N-terminal fragments induced apo

关键词： N-Terminal Fragment Apoptosis Caspases Human Prostate Cancer Cells

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