Inauhzin(c) Inactivates c-Myc Independently of p53

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(c) targets c-Myc activity in human lymphoma cells.

[1]  Xiang Zhou,et al.  The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress , 2014, eLife.

[2]  Xiaoping Zhou,et al.  Ribosomal Proteins L5 and L11 Cooperatively Inactivate c-Myc via RNA-induced Silencing Complex , 2013, Oncogene.

[3]  Hao Li,et al.  Ago1 Interacts with RNA Polymerase II and Binds to the Promoters of Actively Transcribed Genes in Human Cancer Cells , 2013, PLoS genetics.

[4]  Hua Lu,et al.  Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents. , 2013, Neoplasia.

[5]  Xiaoping Zhou,et al.  Global Effect of Inauhzin on Human p53-Responsive Transcriptome , 2012, PloS one.

[6]  Hua Lu,et al.  Structure and Activity Analysis of Inauhzin Analogs as Novel Antitumor Compounds That Induce p53 and Inhibit Cell Growth , 2012, PloS one.

[7]  D. Green,et al.  c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells , 2012, Cell.

[8]  L. Mayo,et al.  Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth , 2012, Cancer biology & therapy.

[9]  S. Meroueh,et al.  A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53 , 2012, EMBO molecular medicine.

[10]  M. Dai,et al.  Ubiquitin- and MDM2 E3 Ligase-independent Proteasomal Turnover of Nucleostemin in Response to GTP Depletion* , 2012, The Journal of Biological Chemistry.

[11]  M. Henriksson,et al.  Identification of Cytotoxic Drugs That Selectively Target Tumor Cells with MYC Overexpression , 2011, PloS one.

[12]  Hua Lu,et al.  Autoregulatory Suppression of c-Myc by miR-185-3p* , 2011, The Journal of Biological Chemistry.

[13]  M. Dai,et al.  Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress , 2011, Molecular and Cellular Biology.

[14]  D. Hanahan,et al.  Endogenous Myc maintains the tumor microenvironment. , 2011, Genes & development.

[15]  I. Gérin,et al.  Roles for miRNA-378/378* in adipocyte gene expression and lipogenesis. , 2010, American journal of physiology. Endocrinology and metabolism.

[16]  Y. Pilpel,et al.  p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC , 2010, Cell Death and Differentiation.

[17]  Michael D. Cole,et al.  Upregulation of c-MYC in cis through a Large Chromatin Loop Linked to a Cancer Risk-Associated Single-Nucleotide Polymorphism in Colorectal Cancer Cells , 2010, Molecular and Cellular Biology.

[18]  C. Dang,et al.  MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities , 2009, Clinical Cancer Research.

[19]  Oliver Hofmann,et al.  miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. , 2009, Molecular cell.

[20]  Hailong Wu,et al.  p53 represses c-Myc through induction of the tumor suppressor miR-145 , 2009, Proceedings of the National Academy of Sciences.

[21]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[22]  R. Eisenman,et al.  Myc's broad reach. , 2008, Genes & development.

[23]  G. Evan,et al.  Modelling Myc inhibition as a cancer therapy , 2008, Nature.

[24]  M. Dai,et al.  Mycophenolic Acid Activation of p53 Requires Ribosomal Proteins L5 and L11* , 2008, Journal of Biological Chemistry.

[25]  M. Dai,et al.  Aberrant Expression of Nucleostemin Activates p53 and Induces Cell Cycle Arrest via Inhibition of MDM2 , 2008, Molecular and Cellular Biology.

[26]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[27]  M. Dai,et al.  Inhibition of c‐Myc activity by ribosomal protein L11 , 2007, The EMBO journal.

[28]  M. Dai,et al.  Balance of Yin and Yang: ubiquitylation-mediated regulation of p53 and c-Myc. , 2006, Neoplasia.

[29]  David P. Bartel,et al.  Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes , 2005, Cell.

[30]  Anne Gatignol,et al.  TRBP, a regulator of cellular PKR and HIV‐1 virus expression, interacts with Dicer and functions in RNA silencing , 2005, EMBO reports.

[31]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[32]  M. Dai,et al.  Inhibition of MDM2-mediated p53 Ubiquitination and Degradation by Ribosomal Protein L5* , 2004, Journal of Biological Chemistry.

[33]  Y. Qi,et al.  p19ARF directly and differentially controls the functions of c-Myc independently of p53 , 2004, Nature.

[34]  M. Dai,et al.  Ribosomal Protein L23 Activates p53 by Inhibiting MDM2 Function in Response to Ribosomal Perturbation but Not to Translation Inhibition , 2004, Molecular and Cellular Biology.

[35]  K. Itahana,et al.  Inhibition of HDM2 and Activation of p53 by Ribosomal Protein L23 , 2004, Molecular and Cellular Biology.

[36]  A. Gartel,et al.  Myc-ARF (Alternate Reading Frame) Interaction Inhibits the Functions of Myc* , 2004, Journal of Biological Chemistry.

[37]  G. Evan,et al.  Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia , 2004, Oncogene.

[38]  T. Allio,et al.  Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway , 2003, Molecular and Cellular Biology.

[39]  M. Kubbutat,et al.  Regulation of HDM2 activity by the ribosomal protein L11. , 2003, Cancer cell.

[40]  Kenneth Chu,et al.  Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC , 2002, Science.

[41]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[42]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[43]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[44]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[45]  Charles J. Sherr,et al.  Nucleolar Arf sequesters Mdm2 and activates p53 , 1999, Nature Cell Biology.

[46]  R. Honda,et al.  Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53 , 1999, The EMBO journal.

[47]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[48]  O. Yoshida,et al.  Enhancement of sensitivity of urinary bladder tumor cells to cisplatin by c‐myc antisense oligonucleotide , 1994, Cancer.

[49]  S. Howell,et al.  In vitro modulation of cisplatin accumulation in human ovarian carcinoma cells by pharmacologic alteration of microtubules. , 1993, The Journal of clinical investigation.

[50]  E. Prochownik,et al.  Modulation of cis-platinum resistance in Friend erythroleukemia cells by c-myc. , 1991, Cancer research.

[51]  P. Twentyman,et al.  Radiation response of human lung cancer cells with inherent and acquired resistance to cisplatin. , 1991, International journal of radiation oncology, biology, physics.

[52]  A. Berns,et al.  Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally , 1991, Molecular and cellular biology.

[53]  M. Shibuya,et al.  Resistance to anticancer drugs in NIH3T3 cells transfected with c-myc and/or c-H-ras genes. , 1991, British Journal of Cancer.

[54]  Y. Lu,et al.  Differential oncogene amplification in tumor cells from a patient treated with cisplatin and 5-fluorouracil. , 1990, European journal of cancer.

[55]  A. Pa,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990 .

[56]  S. Howell,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990, Cancer cells.

[57]  Eric Wickstrom,et al.  A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1 , 1987, Nature.

[58]  M. Cole.  The myc oncogene: its role in transformation and differentiation. , 1986, Annual review of genetics.