Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells

Leukemia volume 16, pages 608–616 (2002)Cite this article

Abstract

Cellular stressors induce various outcomes including inhibition of cell proliferation and cell death. Sodium salicylate (SA), a plant stress hormone, can suppress the proliferation or cause apoptosis in certain mammalian cancer cells. Plant stress hormones are activators of cellular responses, including cell death, to diverse stress situations in plants. Thus, we hypothesized that plant stress hormones share the ability to adversely affect cancer cells. We found that the plant stress hormone SA suppressed proliferation of lymphoblastic leukemia, prostate, breast and melanoma human cancer cells. Jasmonic acid (JA), a plant stress hormone belonging to the Jasmonate family, induced death in lymphoblastic leukemia cells and caused suppression of cell proliferation in the other human cancer cells mentioned above. Another member of the Jasmonate family, methyl jasmonate (MJ), induced death in each of the cell lines. Plant stress hormones did not affect normal human lymphocytes, in contrast to their strong effect on lymphoblastic leukemia cells. JA and MJ caused apoptotic death, as determined by characteristic nuclear morphology, flow cytometric DNA profile and elevation of caspase-3 activity. Finally, mice bearing EL-4 lymphoma and treated with MJ, survived for significantly (P = 0.00953) longer periods of time than untreated mice. These findings suggest that plant stress hormones may potentially be a novel class of anti-cancer drugs.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  1. Somozy Z . Radiation response of cell organelles Micron 2000 31: 165–181

    Article  Google Scholar 

  2. Janssen YM, Van Houten B, Borm PJ, Mossman BT . Cell and tissue responses to oxidative damage Lab Invest 1993 69: 261–274

    CAS  PubMed  Google Scholar 

  3. Fujita J . Cold shock response in mammalian cells J Mol Microbiol Biotechnol 1999 1: 243–255

    CAS  PubMed  Google Scholar 

  4. Guzzo J, Jobin MP, Delmas F, Fortier LC, Garmyn D, Tourdot-Marechal R, Lee B, Divies C . Regulation of stress response in Oenococcus oeni as a function of environmental changes and growth phase Int J Food Microbiol 2000 55: 27–31

    Article  CAS  PubMed  Google Scholar 

  5. Davies KJ . The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress IUBMB Life 1999 48: 41–47

    Article  CAS  PubMed  Google Scholar 

  6. Willingham MC . Cytochemical methods for the detection of apoptosis J Histochem Cytochem 1999 47: 1101–1109

    Article  CAS  PubMed  Google Scholar 

  7. Stewart BW . Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators J Cancer Inst 1994 86: 1286–1295

    Article  CAS  Google Scholar 

  8. Arends MJ, Moris RG, Wyllie AH . Apoptosis: the role of the endonuclease Am J Pathol 1990 136: 593–608

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nicholson DW, Thomberry A . Caspases: killer proteases Trends Biochem Sci 1997 22: 299–306

    Article  CAS  PubMed  Google Scholar 

  10. Porter AG, Janicke RU . Emerging roles of caspases-3 in apoptosis Cell Death Differ 1999 6: 99–104

    Article  CAS  PubMed  Google Scholar 

  11. Bailly JD, Skladanowski A, Bettaieb A, Mansat V, Larsen AK, Laurent G . Natural resistance of acute myeloid leukemia cells lines to mitoxantrone is associated with lack of apoptosis Leukemia 1997 11: 1523–1532

    Article  CAS  PubMed  Google Scholar 

  12. Klampfer L, Cammenga J, Wisniewski HG, Nimer SD . Sodium salicylate activates caspases and induces apoptosis of myeloid leukemia cell lines Blood 1999 93: 2386–2394

    CAS  PubMed  Google Scholar 

  13. Schwenger P, Bellosta P, Vietor I, Basilico C, Skolnik EY, Vilček J . Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activation Proc Natl Acad Sci USA 1997 94: 2869–2873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sotiriou C, Lacroix M, Lagneaux L, Berchem G, Body JJ . The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and-11 Anticancer Res 1999 19: 2997–3006

    CAS  PubMed  Google Scholar 

  15. Sembdner G, Parthier B . The biochemistry and the physiological and molecular actions of jasmonates Annu Rev Physiol Plant Mol Biol 1993 44: 569–589

    Article  CAS  Google Scholar 

  16. Farmer EE, Ryan CA . Interplant communication: air-borne methyl jasmonate induces synthesis of proteinase inhibitors in plant leaves Proc Natl Acad Sci USA 1990 87: 7713–7716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mitler R, Lam E . Sacrifice in the face of foes: pathogen-induced programmed cell death in higher plants Trends Microbiol 1996 4: 10–15

    Article  Google Scholar 

  18. Dangl JL, Dietrich RA, Richberg MH . Death don't have no mercy: cell death programs in plant–microbe interactions Plant Cell 1996 8: 1793–1807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Goodman RN, Novacky AJ . The hypersensitive response reaction in plants to pathogens: a resistance phenomenon American Phytopathological Society: St Paul, MN 1994 (Abstr.)

  20. Schwenger P, Alpert D, Skolnik EY, Vilček J . Cell-type-specific activation of c-Jun N-terminal kinase by salicylates J Cell Physiol 1999 179: 109–114

    Article  CAS  PubMed  Google Scholar 

  21. Flescher E, Fingrut O . Suppression of interleukin-2 biosynthesis by three modes of oxidative cellular stress: selective prevention by N-acetyl cysteine Cytokine 2000 12: 495–498

    Article  CAS  PubMed  Google Scholar 

  22. Katzung BG . Nonsteroidal anti-inflammatory drugs; disease-modifying antirheumatic drugs; nonopioid analgesics; drugs used in gout In: Katzung BG (ed.) Basic and Clinical Pharmacology, 7th edn Appleton & Lange: Stamford 1998 p 583

    Google Scholar 

  23. Kopp E, Ghosh S . Inhibition of NF-κB by sodium salicylate and aspirin Science 1994 265: 956–959

    Article  CAS  PubMed  Google Scholar 

  24. Jurivich DA, Sistonen L, Kroes RA, Morimoto I . Effect of sodium salicylate on the human heat shock response Science 1992 255: 1243–1245

    Article  CAS  PubMed  Google Scholar 

  25. Ryals JA, Neuenschwander UH, Willits MG, Molina A, Steiner H-Y, Hunt MD . Systemic acquired resistance Plant Cell 1996 8: 1809–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Abramson SB, Weissmann G . The mechanisms of action of nonsteroidal antiinflammatory drugs Arthritis Rheum 1989 32: 1–9

    Article  CAS  PubMed  Google Scholar 

  27. Morgan G . Non-steroidal anti-inflammatory drugs and the chemoprevention of colorectal and oesophageal cancers Gut 1996 38: 646–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Peleg II, Lubin MF, Cotsonis GA, Clark WS, Wilcox CM . Long-term use of non-steroidal antiinflammatory drugs and other chemopreventors and risk of subsequent colorectal neoplasia Dig Dis Sci 1996 41: 1319–1326

    Article  CAS  PubMed  Google Scholar 

  29. Vainio H, Morgan G, Kleihues P . An international evaluation of the cancer-preventive potential of nonsteroidal anti-inflammatory drugs Cancer Epidemiol Biomarkers Prev 1997 6: 749–753

    CAS  PubMed  Google Scholar 

  30. Shiff SJ, Qiao L, Tsai LL, Rigas B . Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells J Clin Invest 1995 96: 491–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bunce CM, Mountford JC, French PJ, Mole DJ, Durham J, Michell RH, Brown G . Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family Biochem Biophys Acta 1996 1311: 189–198

    Article  PubMed  Google Scholar 

  32. Shiff SJ, Koutsos MI, Qiao L, Rigas B . Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis Exp Cell Res 1996 222: 179–188

    Article  CAS  PubMed  Google Scholar 

  33. Hial V, De Mello MC, Horakova Z, Beaven MA . Antiproliferative activity of anti-inflammatory drugs in two mammalian cell culture lines J Pharmacol Exp Ther 1977 202: 446–454

    CAS  PubMed  Google Scholar 

  34. Wyllie AH . Apoptosis: an overview Br Med Bull 1997 53: 451–465

    Article  CAS  PubMed  Google Scholar 

  35. Bellosillo B, Pique M, Barragan M, Castano E, Villamor N, Colomer D, Montserrat E, Pons G, Gil J . Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells Blood 1998 92: 1406–1414

    CAS  PubMed  Google Scholar 

  36. McDade TP, Perugini RA, Vittimberga FJ Jr, Carrigan RC, Callery MP . Salicylates inhibit NF-kappaB activation and enhance TNF-alpha-induced apoptosis in human pancreatic cancer J Surg Res 1999 83: 56–61

    Article  CAS  PubMed  Google Scholar 

  37. Conconi A, Smerdon MJ, Howe GA, Ryan CA . The octadecanoid signalling pathway in plants mediates a response to ultraviolet radiation Nature 1996 383: 826–829

    Article  CAS  PubMed  Google Scholar 

  38. Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB . Arachidonic acid metabolism Ann Rev Biochem 1986 55: 69–102

    Article  CAS  PubMed  Google Scholar 

  39. D'Onofrio C, Amici C, Puglianiello A, Faraoni I, Lanzilli G, Santoro MG, Bonmassar E . Comparative anti-viral and anti-proliferative activity of PGA1 and PGJ2 against HTLV-I-infected MT-2 cells Int J Cancer 1992 51: 481–488

    Article  CAS  PubMed  Google Scholar 

  40. Gorospe M, Liu Y, Xu Q, Cherst FJ, Holbrook NJ . Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2 Mol Cell Biol 1996 16: 762–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sasaki H, Fukushima M . Prostaglandins in the treatment of cancer Anti-Cancer Drugs 1994 5: 131–138

    Article  CAS  PubMed  Google Scholar 

  42. Herskowitz I . MAP kinase pathways in yeast: for mating and more Cell 1995 80: 187–197

    Article  CAS  PubMed  Google Scholar 

  43. Hirt H . Multiple roles of MAP kinases in plant signal transduction Trends Plant Sci 1997 2: 11–15

    Article  Google Scholar 

  44. Zhang S, Klessig DF . Salicylic acid activates a 48-kD MAP kinase in tobacco Plant Cell 1997 9: 809–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Halliwell B . Free radicals and antioxidants: a personal view Nutr Rev 1994 52: 253–265

    Article  CAS  PubMed  Google Scholar 

  46. Buttke TM, Sandstrom PA . Oxidative stress as a mediator of apoptosis Immunol Today 1994 15: 7–10

    Article  CAS  PubMed  Google Scholar 

  47. Mittler R, Shulaev V, Seskar M, Lam E . Inhibition of programmed cell death in tobacco plants during a pathogen-induced hypersensitive response at low oxygen pressure Plant Cell 1996 8: 1991–2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang Y, Shah J, Klessig DF . Signal perception and transduction in plant defense responses Genes Dev 1997 11: 1621–1639

    Article  CAS  PubMed  Google Scholar 

  49. Mittler R, Feng X, Cohen M . Post-transcriptional suppression of cytosolic ascorbate peroxidase expression during pathogen-induced programmed cell death in tobacco Plant Cell 1998 10: 461–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Prof Daniel Gold for his help with fluorescence microscopy. This work was supported by the Singer and Finghurt Foundations, Israel.

Author information

Authors and Affiliations

  1. Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    O Fingrut & E Flescher

Authors
  1. O Fingrut
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. E Flescher
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fingrut, O., Flescher, E. Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells. Leukemia 16, 608–616 (2002). https://doi.org/10.1038/sj.leu.2402419

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402419

Keywords

Search

Advanced search

Quick links