title: Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. YY1 and BclXL are overexpressed in prostate cancer.
abstract: Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival/anti-apoptotic pathways, such as NF-κB, in cancer cells. We report here that treatment of drug-resistant human prostate carcinoma cell lines with high levels (500-1000 μM) of the NO-donor DETANONOate sensitized the resistant tumor cells to apoptosis by CDDP and the combination was synergistic. We hypothesized that DETANONOate inhibits previously identified NF-κB-regulated resistant factors such as Yin Yang 1 (YY1) and Bcl-2/BclXL. Lysates from tumor cells treated with DETANONOate showed inhibition of YY1 and BclXL expressions. Transfection with either YY1 or BclXL siRNA resulted in the inhibition of both YY1 and BclXL expressions and sensitized the cells to CDDP apoptosis. Mice bearing PC-3 tumor xenografts and treated with the combination of DETANONOate and CDDP resulted in significant inhibition of tumor growth; treatment with single agent alone did not have any effect on tumor growth. Analysis of patients TMA tissues with prostatic cancer revealed higher expression of both YY1 and BclXL as a function of tumor grades and their levels were directly correlated. Thus, both YY1 and BclXL are potential prognostic biomarkers. Overall, the above findings suggest that one mechanism of DETANONOate-induced sensitization of resistant tumor cells to CDDP correlated with the inhibition of NF-κB and its targets YY1 and BclXL. The examination of the combination of NO donors and cytotoxic therapy in the treatment of resistant prostate cancer may be warranted.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.forename: Stavroula
authors.initials: S
authors.lastname: Baritaki
authors.forename: Guillermina
authors.initials: G
authors.lastname: Baay-Guzman
authors.forename: Marco A
authors.initials: MA
authors.lastname: Hernandez-Luna
authors.forename: Angeles
authors.initials: A
authors.lastname: Hernandez-Cueto
authors.forename: Mario I
authors.initials: MI
authors.lastname: Vega
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051020:bcl-X Protein; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine