title: Inhibition of tumor growth and sensitization to chemotherapy by RNA interference targeting interleukin-6 in the androgen-independent human prostate cancer PC3 model.
abstract: The objective of the present study was to investigate the inhibitory effects of interleukin-6 (IL-6) secretion by androgen-independent human prostate cancer PC3 cells on their growth and chemosensitivity. In this study, we established PC3 in which the expression vector containing short hairpin RNA (shRNA) targeting IL-6 was introduced (PC3/sh-IL6). Changes in the growth and sensitivity to docetaxel in PC3/sh-IL6 were compared with those in PC3 transfected with control vector alone (PC3/Co). Concentration of IL-6 in the culture supernatant from PC3/sh-IL6 was approximately 20% of that from PC3/Co. Both in vitro and in vivo, the growth of PC3/sh-IL-6 was significantly inferior to that of PC3/Co, accompanying downregulation of Bcl-2, Bcl-xL, phosphorylated Akt, p44/42 mitogen-activated protein kinase, and signal transducers and activation of transcription 3 in PC3/sh-IL-6 compared with that in PC3/Co. Despite the higher sensitivity of PC3/sh-IL6 to docetaxel than that of PC3/Co, the secretion of IL-6 by both cell lines was increased after treatment with docetaxel due to the formation of positive autocrine loops between these cell lines and NFκB signaling pathways. Furthermore, combined treatment with the proteasome inhibitor bortezomib, which completely inhibited the docetaxel-induced IL-6 secretion via the inactivation of NFκB signaling, resulted in the marked sensitization of these cell lines to docetaxel both in vitro and in vivo. These findings suggest that suppressed IL-6 secretion using shRNA, either alone or in combination with docetaxel and bortezomib, could be a useful therapeutic strategy against androgen-independent prostate cancer.
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Iori
authors.initials: I
authors.lastname: Sakai
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyake
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Terakawa
authors.forename: Masato
authors.initials: M
authors.lastname: Fujisawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use; D034741:RNA, Small Interfering; D043823:Taxoids / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D000077143:Docetaxel; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D034741:RNA, Small Interfering; D043823:Taxoids; D000093242:Interleukin-6 Inhibitors