Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
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Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

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Τετάρτη 25 Ιουλίου 2018

Inhibition of ER stress-related IRE1α/CREB/NLRP1 pathway promotes the apoptosis of human chronic myelogenous leukemia cell

Publication date: September 2018

Source: Molecular Immunology, Volume 101

Author(s): Zheng Xu, Huirui Wang, Suhua Wei, Zhencheng Wang, Guanghou Ji

Abstract

Endoplasmic reticulum (ER) stress is induced in chronic myelogenous leukemia (CML) cells. As an important sensor of ER stress, inositol-requiring protein-1α (IRE1α) promotes the survival of acute myeloid leukemia. NLRP1 inflammasome activation promotes metastatic melanoma growth and that IRE1α can increase NLRP1 inflammasome gene expression. This study aimed to investigate the role and molecular mechanism of IRE1α in CML cell growth. We found that overexpression of IRE1α or NLRP1 significantly promoted the proliferation and decreased the apoptosis of CML cells, whereas downregulation of these two genes showed the opposite effects. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, reduced the expression of IRE1α and NLRP1. IRE1α elevated NLRP1 expression via cAMP responsive element binding protein (CREB) phosphorylation. NLRP1 inflammasome was activated in CML cells and its activation partly reversed ER stress inhibitor-induced cell apoptosis. Furthermore, inhibition of IRE1α/NLRP1 pathway sensitized CML cells to imatinib-mediated apoptosis. Additionally, IRE1α expression was elevated and NLRP1 inflammasome was activated in primary cells from CML patients. Downregulation of IRE1α or NLRP1 suppressed the proliferation and elevated the apoptosis of primary CML cells. Collectively, this study demonstrated that the IRE1α/CREB/NLRP1 pathway contributes to the progression of CML and the development of imatinib resistance. Hence, targeting ER stress-related IRE1α expression or NLRP1 inflammasome activation may block CML development.



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