title: Imiquimod induces ER stress and Ca(2+) influx independently of TLR7 and TLR8.
abstract: Endoplasmic reticulum (ER) stress is a physiological response to protein overload or misfolded proteins in the ER. Certain anti-cancer drugs, e.g. bortezomib and nelfinavir, induce ER stress implying that this could be a successful therapeutic strategy against several forms of cancer. To find novel ER-stress inducers we screened a panel of natural and synthetic Toll-like receptor (TLR) agonists against human keratinocytes and identified the anti-cancer drug imiquimod (IMQ) as a potent inducer of ER stress. Other TLR7 and TLR8 agonists, including resiquimod and gardiquimod, did not induce ER stress, demonstrating that IMQ induces ER stress independently of TLR7 and TLR8. We further confirmed this by showing that IMQ could still induce ER stress in mouse Tlr7(-/-) cells. IMQ also induced a rapid and transient influx of extracellular Ca(2+) together with the release of Ca(2+) from internal stores. Depletion of Ca(2+) from the ER is a known cause of ER stress suggesting that IMQ induces ER stress via depletion of ER Ca(2+). The ER-stress inducing property of IMQ is possibly of importance for its efficacy in treating basal cell carcinoma, in situ melanoma, and squamous cell carcinoma. Our data could potentially be harnessed for rational design of even more potent ER-stress inducers and new anti-cancer drugs.
authors.affiliation: Unit of Experimental Rheumatology, Center for Molecular Medicine, L8:04, Karolinska University Hospital, Karolinska Institutet, Sjukhusringen 6, SE-171 76, Stockholm, Sweden.
authors.forename: William A
authors.initials: WA
authors.lastname: Nyberg
authors.affiliation: Unit of Experimental Rheumatology, Center for Molecular Medicine, L8:04, Karolinska University Hospital, Karolinska Institutet, Sjukhusringen 6, SE-171 76, Stockholm, Sweden. Electronic address: alexander.espinosa@ki.se.
authors.forename: Alexander
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000077271:Imiquimod; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D000077271:Imiquimod; D002118:Calcium
keywords: Ca(2+) influx; Endoplasmic-reticulum stress; Imidazoquinolines; Imiquimod; Toll-like receptor