Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis
Open Access
- 1 June 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (6), 1604-1614
- https://doi.org/10.1158/1535-7163.mct-07-2424
Abstract
Pinitol (3-O-methyl-chiroinositol), a component of traditional Ayurvedic medicine (talisapatra), has been shown to exhibit anti-inflammatory and antidiabetic activities through undefined mechanisms. Because the transcription factor nuclear factor-κB (NF-κB) has been linked with inflammatory diseases, including insulin resistance, we hypothesized that pinitol must mediate its effects through modulation of NF-κB activation pathway. We found that pinitol suppressed NF-κB activation induced by inflammatory stimuli and carcinogens. This suppression was not specific to cell type. Besides inducible, pinitol also abrogated constitutive NF-κB activation noted in most tumor cells. The suppression of NF-κB activation by pinitol occurred through inhibition of the activation of IκBα kinase, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Pinitol also suppressed the NF-κB reporter activity induced by tumor necrosis factor receptor (TNFR)-1, TNFR-associated death domain, TNFR-associated factor-2, transforming growth factor-β–activated kinase-1 (TAK-1)/TAK1-binding protein-1, and IκBα kinase but not that induced by p65. The inhibition of NF-κB activation thereby led to down-regulation of gene products involved in inflammation (cyclooxygenase-2), proliferation (cyclin D1 and c-myc), invasion (matrix metalloproteinase-9), angiogenesis (vascular endothelial growth factor), and cell survival (cIAP1, cIAP2, X-linked inhibitor apoptosis protein, Bcl-2, and Bcl-xL). Suppression of these gene products by pinitol enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results show that pinitol inhibits the NF-κB activation pathway, which may explain its ability to suppress inflammatory cellular responses. [Mol Cancer Ther 2008;7(6):1604–14]Keywords
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