title: Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis.
abstract: We previously described that cathepsin E specifically induces growth arrest and apoptosis in several human prostate cancer cell lines in vitro by catalyzing the proteolytic release of soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from the tumor cell surface. It also prevents tumor growth and metastasis in vivo through multiple mechanisms, including induction of apoptosis, angiogenesis inhibition and enhanced immune responses. Using the prostate cancer cell line PPC-1, which is relatively resistant to cell death by doxorubicin (40-50% cytotoxicity), we first report that a combination treatment with cathepsin E can overcome resistance of the cells to this agent. In vitro studies showed that combined treatment of PPC-1 cells with the two agents synergistically induces viability loss, mainly owing to down-regulation of a short form of the FLICE inhibitory protein FLIP. The enhanced antitumor activity was corroborated by in vivo studies with athymic mice bearing PPC-1 xenografts. Intratumoral application of cathepsin E in doxorubicin-treated mice results in tumor cell apoptosis and tumor regression in xenografts by enhanced TRAIL-induced apoptosis through doxorubicin-induced c-FLIP down-regulation and by a decrease in tumor cell proliferation. These results indicate that combination of cathepsin E and doxorubicin is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant prostate cancer PPC-1 cells, thus indicating therapeutic potential for clinical use.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasukochi
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kawakubo
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020059:Cathepsin E / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D004317:Doxorubicin; D020059:Cathepsin E; C533927:Ctse protein, rat