title: Rapamycin reverses TLR4 signaling-triggered tumor apoptosis resistance by disrupting Akt-mediated Bcl-xL upregulation.
abstract: Toll-like receptor 4 (TLR4) signaling in tumor cells can promote tumor escape and tumor progression, for which TLR4-triggered resistance of tumor cells to apoptosis has been proposed as one of the mechanisms. Rapamycin is an immunosuppressant agent widely used for treatment of transplantation rejection and autoimmune diseases, and recently used for cancer therapy. However, the underlying mechanisms responsible for antitumor effects of rapamycin remain to be fully elucidated. Here we report that rapamycin can reverse TLR4-triggered resistance of colon cancer cells to oxaloplatin- or doxorubicin-induced apoptosis by disrupting Akt and subsequent NF-kappaB activation, suppressing upregulation of anti-apoptotic protein Bcl-xL. Furthermore, Akt/NF-kappaB inhibitors also reverses the apoptosis resistance, accordingly, Akt constitutive activation rescues NF-kappaB activation and Bcl-xL expression in rapamycin-pretreated colon cancer cells, suggesting Akt disruption is critical to the process. Therefore, rapamycin may abrogate TLR4-triggered tumor apoptosis resistance by inhibiting Akt/NF-kappaB pathways and Bcl-xL expression, providing experimental evidence for the anti-tumor effect of rapamycin.
authors.affiliation: Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Sun
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Liu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology*; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051020:bcl-X Protein; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus