Planta Med 2009; 75(13): 1423-1426
DOI: 10.1055/s-0029-1185805
Pharmacology
Letter
© Georg Thieme Verlag KG Stuttgart · New York

The Phytohormone Auxin Induces G1 Cell-Cycle Arrest of Human Tumor Cells

Katja Ester1 , Mirna Ćurković-Perica2 , Marijeta Kralj1
  • 1Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • 2Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Further Information

Publication History

received March 5, 2009 revised May 11, 2009

accepted May 14, 2009

Publication Date:
22 June 2009 (online)

Abstract

The plant hormone auxin is the key regulator of plant growth and development. Auxin regulates transcription of plant genes by targeting degradation of transcriptional repressor proteins Aux/IAA. While there are many reports describing its potential to modulate human cell functions, the majority are based on auxin action following enzymatic activation. A study focused on auxin alone and its antiproliferative potential, with emphasis on modulation of the cell cycle, has not been performed. Therefore, we analyzed tumor growth inhibitory effects and the cell-cycle perturbations of natural (IAA, IBA) and synthetic (NAA, 2,4-D) auxins. All derivatives showed cytostatic effects on selected human tumor cell lines. The cell-cycle analysis revealed that IAA and 2,4-D induce strong G1 arrest, along with a drastic decrease in the percentage of S-phase cells in MCF-7 cell line. This phenomenon demonstrates that auxins may have novel, unexploited antitumor potential and should be further investigated.

References

  • 1 Goldsmith M H. Cellular signaling: new insights into the action of the plant growth hormone auxin.  Proc Natl Acad Sci USA. 1993;  90 11442-11445
  • 2 Guilfoyle T. Plant biology: sticking with auxin.  Nature. 2007;  446 621-622
  • 3 Mockaitis K, Estelle M. Auxin receptors and plant development: a new signaling paradigm.  Annu Rev Cell Dev Biol. 2008;  24 55-80
  • 4 Gordon S A, Barr S, Fry R JM. Origin of urinary auxin in the germfree and conventional mouse.  Am J Physiol. 1972;  222 399-403
  • 5 Shimojo E, Yamaguchi S, Murofushi N. Increase of indole-3-acetic acid in human esophageal cancer tissue.  Proc Jpn Acad. 1997;  73 182-185
  • 6 Vesely D L, Hudson J L, Pipkin Jr J L, Pack L D, Meiners S E. Plant growth-promoting hormones activate mammalian guanylate cyclase activity.  Endocrinology. 1985;  116 1887-1892
  • 7 Pavlica M, Papeš D, Nagy B. 2,4-Dichlorophenoxyacetic acid causes chromatin and chromosome abnormalities in plant cells and mutation in cultured mammalian cells.  Mutat Res. 1991;  263 77-81
  • 8 de Melo M P, de Lima T M, Pithon-Curi T C, Curi R. The mechanism of indole acetic acid cytotoxicity.  Toxicol Lett. 2004;  148 103-111
  • 9 Folkes L K, Wardman P. Oxidative activation of indole-3-acetic acids to cytotoxic species- a potential new role for plant auxins in cancer therapy.  Biochem Pharmacol. 2001;  61 129-136
  • 10 Furukawa S, Usuda K, Abe M, Hayashi S, Ogawa I. Indole-3-acetic acid induces microencephaly in mouse fetuses.  Exp Toxicol Pathol. 2007;  59 43-52
  • 11 Huang C, Liu L Y, Song T S, Ni L, Yang L, Hu X Y, Hu J S, Song L P, Luo Y, Si L S. Apoptosis of pancreatic cancer BXPC‐3 cells induced by indole-3-acetic acid in combination with horseradish peroxidase.  World J Gastroenterol. 2005;  11 4519-4523
  • 12 Kim D S, Jeon S E, Jeong Y M, Kim S Y, Kwon S B, Park K C. Hydrogen peroxide is a mediator of indole-3-acetic acid/horseradish peroxidase-induced apoptosis.  FEBS Lett. 2006;  580 1439-1446
  • 13 Greco O, Rossiter S, Kanthou C, Folkes L K, Wardman P, Tozer G M, Dachs G U. Horseradish peroxidase-mediated gene therapy: choice of prodrugs in oxic and anoxic tumor conditions.  Mol Cancer Ther. 2001;  1 151-160
  • 14 Kim D S, Kim S Y, Jeong Y M, Jeon S E, Kim M K, Kwon S B, Na J I, Park K C. Light-activated indole-3-acetic acid induces apoptosis in G361 human melanoma cells.  Biol Pharm Bull. 2006;  29 2404-2409
  • 15 Folkes L K, Wardman P. Enhancing the efficacy of photodynamic cancer therapy by radicals from plant auxin (indole-3-acetic acid).  Cancer Res. 2003;  63 776-779
  • 16 Tan X, Calderon-Villalobos L I, Sharon M, Zheng C, Robinson C V, Estelle M, Zheng N. Mechanism of auxin perception by the TIR1 ubiquitin ligase.  Nature. 2007;  446 640-645
  • 17 Tan X, Zheng N. Hormone signaling through protein destruction: a lesson from plants.  Am J Physiol Endocrinol Metab. 2009;  296 223-227
  • 18 Tuschl H, Schwab C E. The use of flow cytometric methods in acute and long-term in vitro testing.  Toxicol In Vitro. 2005;  19 845-852
  • 19 Himanen K, Boucheron E, Vanneste S, de Almeida Engler J, Inzé D, Beeckman T. Auxin-mediated cell cycle activation during early lateral root initiation.  Plant Cell. 2002;  14 2339-2351
  • 20 David K M, Couch D, Braun N, Brown S, Grosclaude J, Perrot-Rechenmann C. The auxin-binding protein 1 is essential for the control of cell cycle.  Plant J. 2007;  50 197-206
  • 21 Bertosa B, Kojić-Prodić B, Wade R C, Tomić S. Mechanism of auxin interaction with Auxin Binding Protein (ABP1): a molecular dynamics simulation study.  Biophys J. 2008;  94 27-37
  • 22 Shin J S, Hong S W, Lee S L, Kim T H, Park I C, An S K, Lee W K, Lim J S, Kim K I, Yang Y, Lee S S, Jin D H, Lee M S. Serum starvation induces G1 arrest through suppression of Skp2-CDK2 and CDK4 in SK‐OV‐3 cells.  Int J Oncol. 2008;  32 435-439
  • 23 Frescas D, Pagano M. Deregulated proteolysis by the F‐box proteins SKP2 and beta-TrCP: tipping the scales of cancer.  Nat Rev Cancer. 2008;  8 438-449
  • 24 Petroski M D, Deshaies R J. Function and regulation of cullin-RING ubiquitin ligases.  Nat Rev Mol Cell Biol. 2005;  6 9-20
  • 25 Garrenton L S, Braunwarth A, Irniger S, Hurt E, Künzler M, Thorner J. Nucleus-specific and cell cycle-regulated degradation of MAPK scaffold protein Ste5 contributes to the control of signaling competence.  Mol Cell Biol. 2009;  29 582-601
  • 26 Supek F, Kralj M, Marjanović M, Šuman L, Šmuc T, Krizmanić I, Žinić B. Atypical cytostatic mechanism of N‐1-sulfonylcytosine derivatives determined by in vitro screening and computational analysis.  Invest New Drugs. 2008;  26 97-110
  • 27 Dzimbeg G, Zorc B, Kralj M, Ester K, Pavelić K, Andrei G, Snoeck R, Balzarini J, De Clercq E, Mintas M. The novel primaquine derivatives of N-alkyl, cycloalkyl or aryl urea: synthesis, cytostatic and antiviral activity evaluations.  Eur J Med Chem. 2008;  43 1180-1187

Dr. sc. Katja Ester

Rudjer Boskovic Institute

Division of Molecular Medicine

Bijenicka 54

10002 Zagreb

Croatia

Phone: + 3 85 14 57 12 35

Fax: + 3 85 14 56 10 10

Email: kester@irb.hr

>