title: Silver nanoparticles induce irremediable endoplasmic reticulum stress leading to unfolded protein response dependent apoptosis in breast cancer cells.
abstract: Nowadays, silver nanoparticles (AgNP) are widely used in the medical field mainly for their antibacterial properties. Although some studies report a cytotoxic activity of the particles, the mechanisms involved in AgNP-induced cell death remain to be determined. Herein, we report that AgNP of 2 (AgNP2) and 15 nm (AgNP15) induce apoptosis in human MCF-7 and T-47D breast cancer cells. Treatment with AgNP2and AgNP15led to accumulation and aggregation of misfolded proteins causing an endoplasmic reticulum (ER) stress and activating the unfolded protein response (UPR). The three main ER sensors, PERK, IRE-1α and ATF-6, were rapidly activated in response to AgNP2and AgNP15. Although Grp78 levels remained unchanged, AgNP2and AgNP15induced upregulation of the transcription factors ATF-4 and GADD153/CHOP. Moreover, the initiating caspase-9 and the effector caspase-7 were activated in response to these NPs. The expression levels of the pro-apoptotic BIM and BAD proteins remained unchanged. In contrast, a downregulation of Mcl-1 and xIAP protein expression as well as a processing of PARP were observed. Pharmacological inhibition of PERK kinase and IRE-1 endonuclease activities, as well as inhibition of ER-stress, partially protected cells from AgNP2- and AgNP15-induced apoptosis. Of note, the non-cancerous MCF-10A cells were more resistant to both AgNP2and AgNP15when compared to MCF-7 and T-47D cell lines. Taken together, our results demonstrate that AgNP induce ER stress and can target the UPR-dependent apoptotic pathway in MCF-7 and T-47D, which highlights new potential strategies for the treatment of breast cancers.
authors: Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, Institut National de la Recherche Scientifique, Institut Armand-Frappier, 531 Boulevard des Prairies, Room K-138, Laval, Québec, H7V 1B7, Canada. j-christophe.simard@iaf.inrs.ca.
authors: Jean-Christophe
authors: JC
authors: Simard
authors: Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, Institut National de la Recherche Scientifique, Institut Armand-Frappier, 531 Boulevard des Prairies, Room K-138, Laval, Québec, H7V 1B7, Canada.
authors: Isabelle
authors: I
authors: Durocher
authors: Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, Institut National de la Recherche Scientifique, Institut Armand-Frappier, 531 Boulevard des Prairies, Room K-138, Laval, Québec, H7V 1B7, Canada.
authors: Denis
authors: D
authors: Girard
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity; D012834:Silver / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C497109:ATF4 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051701:Activating Transcription Factor 4; D012834:Silver; D053179:Caspase 7; D053453:Caspase 9
keywords: Breast cancer; Endoplasmic reticulum stress; Silver nanoparticles; Unfolded protein response