Targeting the unfolded protein response, XBP1, and the NLRP3 inflammasome in fibrosis and cancer.
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.
Center for Animal Referral and Emergency Services (CARES); Langhorne, PA USA.
Beth
B
Overley-Adamson
Drexel University College of Medicine; Department of Microbiology and Immunology; Philadelphia, PA USA.
Carol M
CM
Artlett
TherimuneX Pharmaceuticals, Inc.; Doylestown, PA USA.
Connie
C
Stephens
Drexel University College of Medicine; Department of Microbiology and Immunology; Philadelphia, PA USA.
Sihem
S
Sassi-Gaha
Doylestown Veterinary Hospital; Doylestown, PA USA.
Ransome D
RD
Weis
Drexel University College of Medicine; Department of Microbiology and Immunology; Philadelphia, PA USA; TherimuneX Pharmaceuticals, Inc.; Doylestown, PA USA.
James D
JD
Thacker
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009369:Neoplasms / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D010865:Pilot Projects; D021382:Protein Sorting Signals / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D021382:Protein Sorting Signals; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse
ER; NLRP3; UPR; XBP1; cancer; chemotherapy; fibrosis; immune; inflammasome; oncogenesis