title: HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells.
abstract: Development of chemoresistance, especially to docetaxel (DTX), is the primary barrier to the cure of castration-resistant prostate cancer but its mechanism is obscure. Here, we report a seminal crosstalk between dying and residual live tumor cells during treatment with DTX that can result in outgrowth of a chemoresistant population. Survival was due to the induction of secretory/cytoplasmic clusterin (sCLU), which is a potent anti-apoptotic protein known to bind and sequester Bax from mitochondria, to prevent caspase 3 activation. sCLU induction in live cells depended on HMGB1 release from dying cells. Supernatants from DTX-treated DU145 tumor cells, which were shown to contain HMGB1, effectively induced sCLU from newly-plated DU145 tumor cells and protected them from DTX toxicity. Addition of anti-HMBG1 to the supernatant or pretreatment of newly-plated DU145 tumor cells with anti-TLR4 or anti-RAGE markedly abrogated sCLU induction and protective effect of the supernatant. Mechanistically, HMGB1 activated NFκB to promote sCLU gene expression and prevented the translocation of activated Bax to mitochondria to block cell death. Importantly, multiple currently-used chemotherapeutic drugs could release HMGB1 from tumor cells. These results suggest that acquisition of chemoresistance may involve the HMGB1/TLR4-RAGE/sCLU pathway triggered by dying cells to provide survival advantage to remnant live tumor cells.
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Gilvary
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Melba M
authors.initials: MM
authors.lastname: Tejera
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Eksioglu
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Immunology Program, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D051152:Clusterin; D024243:HMGB1 Protein; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D020928:Mitogen-Activated Protein Kinases