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The AAPS Journal

, Volume 12, Issue 1, pp 51–60 | Cite as

Small Molecule Modifiers of the microRNA and RNA Interference Pathway

  • Alexander Deiters
Review Article Theme: siRNA and microRNA: From Target Validation to Therapy

Abstract

Recently, the RNA interference (RNAi) pathway has become the target of small molecule inhibitors and activators. RNAi has been well established as a research tool in the sequence-specific silencing of genes in eukaryotic cells and organisms by using exogenous, small, double-stranded RNA molecules of approximately 20 nucleotides. Moreover, a recently discovered post-transcriptional gene regulatory mechanism employs microRNAs (miRNAs), a class of endogenously expressed small RNA molecules, which are processed via the RNAi pathway. The chemical modulation of RNAi has important therapeutic relevance, because a wide range of miRNAs has been linked to a variety of human diseases, especially cancer. Thus, the activation of tumor-suppressive miRNAs and the inhibition of oncogenic miRNAs by small molecules have the potential to provide a fundamentally new approach for the development of cancer therapeutics.

Key words

cancer microRNA RNA RNA interference small molecule 

Notes

Acknowledgments

Financial support from the Department of Chemistry at North Carolina State University and the American Chemical Society (TEVA USA Scholars Grant) is acknowledged. The author apologizes to those researchers whose work could not be discussed due to space limitations. AD is a Beckman Young Investigator, a Cottrell Scholar, and a recipient of an NSF CAREER award.

References

  1. 1.
    Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev. 2006;16(2):203–8.CrossRefPubMedGoogle Scholar
  2. 2.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.CrossRefPubMedGoogle Scholar
  3. 3.
    Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet. 2009;10(2):94–108.CrossRefPubMedGoogle Scholar
  4. 4.
    Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20(5):515–24.CrossRefPubMedGoogle Scholar
  5. 5.
    Filipowicz W. RNAi: the nuts and bolts of the RISC machine. Cell. 2005;122(1):17–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature. 2004;431(7006):343–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Du T, Zamore PD. microPrimer: the biogenesis and function of microRNA. Development. 2005;132(21):4645–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A. 2007;104(23):9667–72.CrossRefPubMedGoogle Scholar
  9. 9.
    Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318(5858):1931–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294(5543):858–62.CrossRefPubMedGoogle Scholar
  12. 12.
    Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294(5543):862–4.CrossRefPubMedGoogle Scholar
  13. 13.
    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.CrossRefPubMedGoogle Scholar
  14. 14.
    Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94(6):776–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Appasani K. MicroRNAs: from basic science to disease biology. Cambridge: Cambridge University Press; 2008.Google Scholar
  16. 16.
    Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell. 2004;16(6):861–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004;432(7014):231–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, et al. The Microprocessor complex mediates the genesis of microRNAs. Nature. 2004;432(7014):235–40.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001;409(6818):363–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 2001;106(1):23–34.CrossRefPubMedGoogle Scholar
  22. 22.
    Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001;293(5531):834–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 2001;15(20):2654–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17(24):3011–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Hammond SM. MicroRNAs as oncogenes. Curr Opin Genet Dev. 2006;16(1):4–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000;404(6775):293–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Hutvagner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297(5589):2056–60.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A. 2006;103(24):9136–41.CrossRefPubMedGoogle Scholar
  29. 29.
    Chan SP, Slack FJ. microRNA-mediated silencing inside P-bodies. RNA Biol. 2006;3(3):97–100.PubMedGoogle Scholar
  30. 30.
    Kong YW, Cannell IG, de Moor CH, Hill K, Garside PG, Hamilton TL, et al. The mechanism of micro-RNA-mediated translation repression is determined by the promoter of the target gene. Proc Natl Acad Sci U S A. 2008;105(26):8866–71.CrossRefPubMedGoogle Scholar
  31. 31.
    Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 2007;17(3):118–26.CrossRefPubMedGoogle Scholar
  32. 32.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99(24):15524–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101(9):2999–3004.CrossRefPubMedGoogle Scholar
  34. 34.
    He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–33.CrossRefPubMedGoogle Scholar
  35. 35.
    Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006;9(6):435–43.CrossRefPubMedGoogle Scholar
  36. 36.
    Shi XB, Tepper CG, deVere White RW. Cancerous miRNAs and their regulation. Cell Cycle. 2008;7(11):1529–38.PubMedGoogle Scholar
  37. 37.
    O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435(7043):839–43.CrossRefPubMedGoogle Scholar
  38. 38.
    Shah YM, Morimura K, Yang Q, Tanabe T, Takagi M, Gonzalez FJ. Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol Cell Biol. 2007;27(12):4238–47.CrossRefPubMedGoogle Scholar
  39. 39.
    Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006;20(16):2202–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454(7200):56–61.CrossRefPubMedGoogle Scholar
  41. 41.
    Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A, et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature. 2009;459(7249):1010–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.CrossRefPubMedGoogle Scholar
  43. 43.
    Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65(16):7065–70.CrossRefPubMedGoogle Scholar
  44. 44.
    Davies BP, Arenz C. A homogenous assay for micro RNA maturation. Angew Chem Int Ed Engl. 2006;45(33):5550–2.CrossRefPubMedGoogle Scholar
  45. 45.
    Vermeulen A, Behlen L, Reynolds A, Wolfson A, Marshall WS, Karpilow J, et al. The contributions of dsRNA structure to Dicer specificity and efficiency. RNA. 2005;11(5):674–82.CrossRefPubMedGoogle Scholar
  46. 46.
    Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, et al. A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol. 2008;26(8):933–40.CrossRefPubMedGoogle Scholar
  47. 47.
    Gumireddy K, Young DD, Xiong X, Hogenesch JB, Huang Q, Deiters A. Small-molecule inhibitors of microrna miR-21 function. Angew Chem Int Ed Engl. 2008;47(39):7482–4.CrossRefPubMedGoogle Scholar
  48. 48.
    Bhanot SK, Singh M, Chatterjee NR. The chemical and biological aspects of fluoroquinolones: reality and dreams. Curr Pharm Des. 2001;7(5):311–35.CrossRefPubMedGoogle Scholar
  49. 49.
    Katoh T, Suzuki T. Specific residues at every third position of siRNA shape its efficient RNAi activity. Nucleic Acids Res. 2007;35(4):e27.CrossRefPubMedGoogle Scholar
  50. 50.
    Chiu YL, Dinesh CU, Chu CY, Ali A, Brown KM, Cao H, et al. Dissecting RNA-interference pathway with small molecules. Chem Biol. 2005;12(6):643–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, et al. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun. 2005;334(4):1351–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803.CrossRefPubMedGoogle Scholar
  53. 53.
    Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007;120(5):1046–54.CrossRefPubMedGoogle Scholar
  54. 54.
    Tran N, McLean T, Zhang X, Zhao CJ, Thomson JM, O'Brien C, et al. MicroRNA expression profiles in head and neck cancer cell lines. Biochem Biophys Res Commun. 2007;358(1):12–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Lui WO, Pourmand N, Patterson BK, Fire A. Patterns of known and novel small RNAs in human cervical cancer. Cancer Res. 2007;67(13):6031–43.CrossRefPubMedGoogle Scholar
  56. 56.
    Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128–36.CrossRefPubMedGoogle Scholar
  57. 57.
    Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67(18):8699–707.CrossRefPubMedGoogle Scholar
  58. 58.
    Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–58.CrossRefPubMedGoogle Scholar
  59. 59.
    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–33.CrossRefPubMedGoogle Scholar
  60. 60.
    Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res. 2007;67(19):8994–9000.CrossRefPubMedGoogle Scholar
  61. 61.
    Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK, et al. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer. 2006;5:24.CrossRefPubMedGoogle Scholar
  62. 62.
    Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM. Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res. 2009;37(8):2584–95.CrossRefPubMedGoogle Scholar
  63. 63.
    Bhat-Nakshatri P, Wang G, Collins NR, Thomson MJ, Geistlinger TR, Carroll JS, et al. Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res. 2009;37(14):4850–61.CrossRefPubMedGoogle Scholar
  64. 64.
    Rossi L, Bonmassar E, Faraoni I. Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. Pharmacol Res. 2007;56(3):248–53.CrossRefPubMedGoogle Scholar
  65. 65.
    Thomas JR, Hergenrother PJ. Targeting RNA with small molecules. Chem Rev. 2008;108(4):1171–224.CrossRefPubMedGoogle Scholar
  66. 66.
    Tor Y. Targeting RNA with small molecules. ChemBioChem. 2003;4(10):998–1007.CrossRefPubMedGoogle Scholar
  67. 67.
    Gooch BD, Beal PA. Recognition of duplex RNA by helix-threading peptides. J Am Chem Soc. 2004;126(34):10603–10.CrossRefPubMedGoogle Scholar
  68. 68.
    Henn A, Joachimi A, Goncalves DP, Monchaud D, Teulade-Fichou MP, Sanders JK, et al. Inhibition of dicing of guanosine-rich shRNAs by quadruplex-binding compounds. ChemBioChem. 2008;9(16):2722–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Rezler EM, Bearss DJ, Hurley LH. Telomere inhibition and telomere disruption as processes for drug targeting. Annu Rev Pharmacol Toxicol. 2003;43:359–79.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Department of ChemistryNorth Carolina State UniversityRaleighUSA

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