Abstract
Despite recent biomedical improvements in treating Multiple Myeloma (MM), the disease still remains incurable. Toll like receptors (TLRs) provide a link between innate and adaptive immune responses and hence potentially correlate inflammation to cancer. Although the regulatory role of TLRs in MM has been under investigation the underlying mechanisms remain unclear. In this study we assayed the function of TLR4 in MM cell lines and in MM patients’ samples. We found that lipopolysaccharide-mediated TLR4 activation increased MM cells proliferation and decreased endoplasmic reticulum (ER) stress-induced apoptosis. Furthermore, we observed that either the endogenous CHOP expression or the ER stress-mediated CHOP induction, were suppressed by TLR4 activation or its overexpression in MM cell lines; TLR4 induction also suppressed ER stress-induced apoptotic signals. In support, TLR4 gene expression silencing in MM cell lines significantly decreased cell proliferation and promoted CHOP and ATF4 upregulation. TLR4 activation was also able to partially abrogate the effect of bortezomib in MM cell lines by suppressing PERK, ATF4 and phospho-eIF2A. We suggest that TLR4-mediated disruption of ER stress responses contributes to MM cells proliferation and suppresses ER-dependent death signals.
Highlights
Of intense DNA damage or endoplasmic reticulum (ER) stress[8]
Previous studies have implicated TLR4 signaling in MM cells survival[26,27,28,29,30,31,32], our study investigated the role of TLR4 in malignant plasma cells survival through its potential interaction with the integrated stress response components
Our results provide evidence that LPS-mediated TLR4 stimulation promotes myeloma cell growth and survival by suppressing apoptosis associated with integrated stress response and UPR activation through PERK-CHOP signaling
Summary
Of intense DNA damage or ER stress[8]. Upon increased ER stress, the ATF6 and PERK/eIF2A are activated leading to the induction of ATF4 translation and to CHOP upregulation[9,10,11]. We found that pre-treatment of JJN3 and H929 cells with the TLR4 inhibitor (0.5 μg/ml) significantly abrogated the viability effects of LPS (1 μg/ml) by ~40%, and 25%, respectively while in U266 and L363 cells that express low endogenous levels of TLR4 levels, the reduction was less pronounced ~10%, (p = NS) (Fig. 2d).
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