title: Inauhzin(c) inactivates c-Myc independently of p53.
abstract: Oncogene MYC is deregulated in many human cancers, especially in lymphoma. Previously, we showed that inauhzin (INZ) activates p53 and inhibits tumor growth. However, whether INZ could suppress cancer cell growth independently of p53 activity is still elusive. Here, we report that INZ(c), a second generation of INZ, suppresses c-Myc activity and thus inhibits growth of human lymphoma cells in a p53-independent manner. INZ(c) treatment decreased c-Myc expression at both mRNA and protein level, and suppressed c-Myc transcriptional activity in human Burkitt's lymphoma Raji cells with mutant p53. Also, we showed that overexpressing ectopic c-Myc rescues the inhibition of cell proliferation by INZ(c) in Raji cells, implicating c-Myc activity is targeted by INZ(c). Interestingly, the effect of INZ(c) on c-Myc expression was impaired by disrupting the targeting of c-Myc mRNA by miRNAs via knockdown of ribosomal protein (RP) L5, RPL11, or Ago2, a subunit of RISC complex, indicating that INZ(c) targets c-Myc via miRNA pathways. These results reveal a new mechanism that INZ
authors.affiliation: a Department of Biochemistry & Molecular Biology and Cancer Center ; Tulane University School of Medicine ; New Orleans , LA USA.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Liao
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Shelya
authors.initials: S
authors.lastname: Zeng
authors.forename: Daniel
authors.initials: D
authors.lastname: Nguyen
authors.forename: Qian
authors.initials: Q
authors.lastname: Hao
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Cao
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D060565:Argonaute Proteins / Q000096:biosynthesis; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010640:Phenothiazines / Q000008:administration & dosage*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012269:Ribosomal Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D007211:Indoles; C489427:MYC protein, human; D010640:Phenothiazines; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C573921:inauzhin; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human
keywords: Dox, doxorubicin; FACS, Fluorescence-activated cell sorting; GTP, guanosine triphosphate; INZ, inauhzin; Inauhzin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, Phosphate Buffered Saline; PI, propidium iodide; RISC, RNA-induced silencing complex; RP, ribosomal protein; RPL11; RPL5; UTR, untranslated region; c-Myc; lymphoma; microRNA; q-RT-PCR, Real-time reverse transcription polymerase chain reaction