Dominant-Negative Constructs of IRE-1alpha as an Effective way to Suppression of Tumor Growth through the Inhibition of Cell Proliferation
DOI:
https://doi.org/10.12970/2308-8044.2015.03.01.5Keywords:
Tumor growth, endoplasmic reticulum stress, inhibition of IRE-1a/ERN1, U87 glioma cells, angiogenesis, apoptosis, cell cycle, tumor suppressors.Abstract
Activation of cell proliferation and angiogenesis as well as the down-regulation of apoptosis are important for tumor growth through pathways of the unfolding protein response/endoplasmic reticulum stress, a fundamental phenomenon for secure protection of cells by maintaining the functional integrity of the endoplasmic reticulum. It is mediated by three sensor and signaling pathways: IRE-1a/ERN1 (inositol-requiring enzyme-1a/endoplasmic reticulum to nuclei 1), ATF6 (activating transcription factor 6), and PERK (double stranded RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). All three arms of the unfolded protein response are important for tumor cell survival and growth especially under hypoxic conditions, but the unfolded protein response signaling is mainly mediated through the ERN1 pathway.The inhibition of ERN1 by its dominant-negative constructs leads to a decrease of tumor growth through suppression of angiogenesis and cell proliferation as well as activation of apoptosis and tumor suppressors. Data concerning the molecular mechanisms of the effect a blockade of ERN1 signaling enzyme has on glioma growth is analyzed, including the expression of genes controlling angiogenesis, cell proliferation, cell cycle, and apoptosis. Moreover, the inhibition of ERN1 endoribonuclease only has more profound effect on the expression of most key regulatory genes as well as on cell proliferation than the blockade of both kinase and endonuclease activity of ERN1 in glioma cells. In conclusion, the inhibition ofERN1/IRE-1alpha coordinately regulated factors involved in tumor growth, lowering expression levels of pro-proliferative, pro-angiogenic and anti-apoptotic factors and enzymes and up-regulated the expression of anti-proliferative, anti-angiogenic and pro-apoptotic factors in a trend towards the level of these transcription factors in normal human astrocytes. These review attempts to summarize recent advances in the role of inhibition of ERN1 signalingby dominant/negative strategies in regulation of proliferation and apoptosis related genes and suppression of tumor growth, which will help to define the best therapeutic targets for the design of potent antitumor drug.
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