Targeting the unfolded protein response, XBP1, and the NLRP3 inflammasome in fibrosis and cancer

Abstract

Increasing health care costs in the US are due in a large part to the increasing prevalence of chronic diseases in an aging population. Current therapeutic strategies for treating chronic diseases alleviate symptoms allowing patients to live longer with these diseases, but they do little, however, to alter the underlying disease course. Recent advances in molecular biology are revealing new drug targets that may significantly alter the course of these diseases and, as a result, offer economic relief from burgeoning health care costs. Endoplasmic reticulum (ER) stress has been implicated as an underlying pathology in many chronic diseases, and, therefore, the development of therapies designed to ameliorate ER stress may yield novel, effective treatment strategies. Herein, we report that X-box binding protein 1 (XBP1) may be one of the earliest proteins engaged in response to ER stress. We show that a new signaling peptide derived from the ER-embedded transient receptor potential calcium channel protein 1 (TRPC1) engages XBP1 upstream of NLRP3 inflammasome-mediated maturation and secretion of IL-1β/IL-18. Moreover, we show that a synthetic homolog of this signaling peptide (Naclynamide™) administered intravenously twice weekly over a 4-week treatment course induced suppuration and evoked partial or complete resolution of lesions associated with a fibrotic granuloma, a lymphosarcoma, and a colo-rectal carcinoma in canine patients. The mode of action for Naclynamide™ as a first-in-class anti-cancer drug candidate is discussed.

The myeloid heat shock transcription factor 1/β‐catenin axis regulates NLR family, pyrin domain‐containing 3 inflammasome activation in mouse liver ischemia/reperfusion injury

“…Indeed, increasing evidence demonstrates that IRE1α activates the innate NLRP3 signaling pathways through promoting thioredoxin‐interacting protein in response to ER stress . Engagement of XBP1 by a signaling peptide targeting the ER receptor triggers NLRP3‐mediated immune response . Our in vivo results revealed an unexpected role of XBP1 in controlling the dynamic cross‐talk with NLRP3 in HSF1‐β‐catenin axis‐mediated immune regulation.…”

“…(46) Engagement of XBP1 by a signaling peptide targeting the ER receptor triggers NLRP3-mediated immune response. (47) Our in vivo results revealed an unexpected role of XBP1 in controlling the dynamic cross-talk with NLRP3 in HSF1-bcatenin axis-mediated immune regulation.…”

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling

“…Notably, inhibition of the NLRP3 inflammasome suppresses cell apoptosis . NLRP3 inflammasome has been demonstrated to participate in the pathogenesis of cardiovascular disorders , metabolic syndrome and cancer . In addition, cytoplasmic expression of NLRP3 is detected in cerebral cortical neurons .…”

Expression of XBP1s in fibroblasts is critical for TiAl6V4 particle‐induced RANKL expression and osteolysis

“…XBP1s has been suggested as a potential target in cancer and fibrotic disease. Blocking XBP1 splicing by inhibition of IRE‐1α could be a promising therapeutic option in multiple myeloma and other cancer types . In addition, XBP1 was also involved in scleroderma, an uncontrolled fibrotic disease of skin and internal organs .…”