Nicotinic acetylcholine receptor signaling regulates inositol‐requiring enzyme 1α activation to protect β‐cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress

Abstract

Aims/Introduction: Under irremediable endoplasmic reticulum (ER) stress, hyperactivated inositol-requiring enzyme 1a (IRE1a) triggers the terminal unfolded protein response (T-UPR), causing crucial cell dysfunction and apoptosis. We hypothesized that nicotinic acetylcholine receptor (nAChR) signaling regulates IRE1a activation to protect b-cells from the T-UPR under ER stress. Materials and Methods: The effects of nicotine on IRE1a activation and key T-UPR markers, thioredoxin-interacting protein and insulin/proinsulin, were analyzed by real-time polymerase chain reaction and western blotting in rat INS-1 and human EndoC-bH1 b-cell lines. Doxycycline-inducible IRE1a overexpression or ER stress agents were used to induce IRE1a activation. An a7 subunit-specific nAChR agonist (PNU-282987) and small interfering ribonucleic acid for a7 subunit-specific nAChR were used to modulate nAChR signaling. Results: Nicotine inhibits the increase in thioredoxin-interacting protein and the decrease in insulin 1/proinsulin expression levels induced by either forced IRE1a hyperactivation or ER stress agents. Nicotine attenuated X-box-binding protein-1 messenger ribonucleic acid site-specific splicing and IRE1a autophosphorylation induced by ER stress. Furthermore, PNU-282987 attenuated T-UPR induction by either forced IRE1a activation or ER stress agents. The effects of nicotine on attenuating thioredoxin-interacting protein and preserving insulin 1 expression levels were attenuated by pharmacological and genetic inhibition of a7 nAChR. Finally, nicotine suppressed apoptosis induced by either forced IRE1a activation or ER stress agents. Conclusions: Our findings suggest that nAChR signaling regulates IRE1a activation to protect b-cells from the T-UPR and apoptosis under ER stress partly through a7 nAChR. Targeting nAChR signaling to inhibit the T-UPR cascade may therefore hold therapeutic promise by thwarting b-cell death in diabetes. homeostasis during both constitutive secretory protein folding and assembly, and under conditions of excessive protein folding demand (i.e., ER stress) 1. Under ER stress, intracellular signaling pathways termed the unfolded protein response (UPR)

YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy

“…In the present study, we showed that nicotine could increase the expression of the ER stress-responsive protein, BiP, through α7-nAChR signaling. The controversial link between nAChR signaling and UPR components has been previously reported in non-tumor cells [26,41]. For example, Srinivasan et al showed that pharmacological chaperoning of nAChR after nicotine treatment could repress ER stress and UPR activation, which in turn resulted in neuroprotection of Neuro-2a cells [41].…”

“…For example, Srinivasan et al showed that pharmacological chaperoning of nAChR after nicotine treatment could repress ER stress and UPR activation, which in turn resulted in neuroprotection of Neuro-2a cells [41]. In addition, Ishibashi et al observed that nicotine suppressed ER stress-induced apoptosis in pancreatic β-cells by regulating UPR activation through α7-nAChR [26]. The detailed mechanisms contributing to this discrepancy have not been well evaluated, and further studies are needed to investigate the role of nAChR in context-specific regulation of UPR signaling upon nicotine treatment in different tissues.…”

“…In oral cancer, nicotine has been shown to stimulate cell proliferation and inhibit apoptosis through α7-nAChR [6,7,24,25]. A recent study showed that α7-nAChR signaling was involved in nicotine-regulated UPR activation in rat and human pancreatic β-cell lines [26]. However, the role of α7-nAChR in the regulation of UPR components, especially BiP, upon nicotine exposure in oral cancer is still under investigation.…”

Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells

“…Imatinib, a tyrosine kinase inhibitor cancer therapeutic linked to improved glycemic control in cancer patients with diabetes, also led to β-cell protection and diabetes prevention in NOD mice. Intriguingly, nicotine also has IRE1α inhibitory properties, rescuing β-cells from ER stress–mediated cell death by activating the nicotinic acetylcholine receptor ( 76 ). Taken together with the new evidence that deletion of IRE1α reduced incidence of diabetes through avoidance of autoantigen production ( 22 ), IRE1α seems to be a promising target for T1D prevention.…”

Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

“…Under remediable ER stress, IRE1α plays a vital role in preserving cell viability and functioning by triggering a frameshift splicing of the X-box Binding Protein 1 ( XBP1 ) mRNA. The translated spliced form XBP1 ( sXBP1 ) transcriptionally upregulates genes to manage protein folding demand and sustain the cell, known as adaptive UPR (A-UPR) [ 8 , 9 , 10 ].…”