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10.18632/oncotarget.13438 http://scihub22266oqcxt.onion/10.18632/oncotarget.13438 C5356634!5356634 !27880732     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27880732 &cmd=llinks): Failed to open stream: HTTP request failed! 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Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells |pdf=|usr=}}{{27880732 }} gab.com Text Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells JO: Oncotarget http://www.kidney.de/pget.php?&tw=1&pmid=27880732 #FOAvip Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that are hallmarks of human cancer. MDSCs inhibit cytotoxic T lymphocytes (CTLs) and NK cell functions to promote tumor immune escape and progression, and therefore are considered key targets in cancer immunotherapy. Recent studies determined a key role of the apoptosis pathways in tumor-induced MDSC homeostasis and it is known that ceramide plays a key role in regulation of mammalian cell apoptosis. In this study, we aimed to determine the efficacy and underlying molecular mechanism of ceramide in suppression of MDSCs. Treatment of tumor-bearing mice with LCL521, a lysosomotropic inhibitor of acid ceramidase, significantly decreased MDSC accumulation in vivo. Using a MDSC-like myeloid cell model, we determined that LCL521 targets lysosomes and increases total cellular C16 ceramide level. Although MDSC-like cells have functional apoptosis pathways, LCL521-induced MDSC death occurs in an apoptosis- and necroptosis-independent mechanism. LCL521 treatment resulted in an increase in the number of autophagic vesicles, heterolysosomes and swollen ERs. Finally, concomitant inhibition of cathepsin B and cathepsin D was required to significantly decrease LCL521-induced cell death. Our observations indicate that LCL521 targets lysosomes to activate cathepsin B and cathepsin D, resulting in interrupted autophagy and ER stress that culminates in MDSC death. Therefore, a ceramidase inhibitor is potentially an effective adjunct therapeutic agent for suppression of MDSCs to enhance the efficacy of CTL-based cancer immunotherapy. Twit Text FOAVip Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells ????Oncotarget http://www.kidney.de/pget.php?&tw=1&pmid=27880732 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27880732 #FOAvip English Wikipedia <ref>{{Cite pmid|27880732 }}</ref> Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells #MMPMID27880732 Liu F ; Li X ; Lu C ; Bai A ; Bielawski J ; Bielawska A ; Marshall B ; Schoenlein PV ; Lebedyeva IO ; Liu K Oncotarget 2016[Dec]; 7 (51 ): 83907-83925 PMID27880732 show ga Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that are hallmarks of human cancer. MDSCs inhibit cytotoxic T lymphocytes (CTLs) and NK cell functions to promote tumor immune escape and progression, and therefore are considered key targets in cancer immunotherapy. Recent studies determined a key role of the apoptosis pathways in tumor-induced MDSC homeostasis and it is known that ceramide plays a key role in regulation of mammalian cell apoptosis. In this study, we aimed to determine the efficacy and underlying molecular mechanism of ceramide in suppression of MDSCs. Treatment of tumor-bearing mice with LCL521, a lysosomotropic inhibitor of acid ceramidase, significantly decreased MDSC accumulation in vivo. Using a MDSC-like myeloid cell model, we determined that LCL521 targets lysosomes and increases total cellular C16 ceramide level. Although MDSC-like cells have functional apoptosis pathways, LCL521-induced MDSC death occurs in an apoptosis- and necroptosis-independent mechanism. LCL521 treatment resulted in an increase in the number of autophagic vesicles, heterolysosomes and swollen ERs. Finally, concomitant inhibition of cathepsin B and cathepsin D was required to significantly decrease LCL521-induced cell death. Our observations indicate that LCL521 targets lysosomes to activate cathepsin B and cathepsin D, resulting in interrupted autophagy and ER stress that culminates in MDSC death. Therefore, a ceramidase inhibitor is potentially an effective adjunct therapeutic agent for suppression of MDSCs to enhance the efficacy of CTL-based cancer immunotherapy. |Acid Ceramidase/antagonists & inhibitors/metabolism [MESH] |Animals [MESH] |Antineoplastic Agents/*pharmacology [MESH] |Autophagy/*drug effects [MESH] |Cathepsin B/*metabolism [MESH] |Cathepsin D/*metabolism [MESH] |Cell Line, Tumor [MESH] |Ceramides/*metabolism [MESH] |Dose-Response Relationship, Drug [MESH] |Endoplasmic Reticulum Stress/*drug effects [MESH] |Enzyme Activation [MESH] |Enzyme Inhibitors/*pharmacology [MESH] |Lysosomes/*drug effects/enzymology/pathology [MESH] |Mice, Inbred BALB C [MESH] |Myeloid-Derived Suppressor Cells/*drug effects/enzymology/pathology [MESH] |Sarcoma/*drug therapy/enzymology/immunology/pathology [MESH] |Signal Transduction/*drug effects [MESH]Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate (epmc).pdf DeepDyve Pubget Overpricing