Skip to main content
SpringerLink
Log in

Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. Recently, VPA was demonstrated to inhibit histone deacetylases (HDACs) class I enzyme at therapeutically relevant concentrations, thereby, mimicking the prototypical histone deacetylase inhibitors, tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA). In the present study, we investigated the cellular effects of VPA, TSA and SAHA on four human melanoma cell lines (WM115, WM266, A375, SK-Mel28) with particular reference to the modulation of regulators of apoptosis, including Bcl-2, BclXL, Mcl-1, Apaf-1, BclXs, NOXA, TRAIL-R1, TRAIL-R2, caspase 8, and survivin). Firstly, we found that VPA induced apoptosis in two of the four human melanoma cell lines, while both TSA and SAHA exhibited an antiproliferative and apoptotic effects in all four cell lines, a different expression of Bcl-2 and BclXL/S occurred. On the other hand, SAHA and VPA modulated differently pro- and anti-apoptotic factors. In particular, the treatment with VPA enhanced the level of expression of survivin only in VPA-resistant cell lines, whereas down-regulation of survivin was induced by VPA and SAHA in VPA-sensitive cells. In the latter, since activation of caspase 8 was documented, a receptor-mediated apoptosis was suggested. Taken together, our results suggest that HDAC inhibitors may represent a promising therapeutic strategy to treat melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997; 389: 349–352.

    Article  PubMed  Google Scholar 

  2. Butler LM, Agus DB, Scher HI, et al.Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitroand in vivo. Cancer Res2000; 60: 5165–5170.

    PubMed  Google Scholar 

  3. Richon VM, Webb Y, Merger R, et al.Second generation hybrid polar compounds are potent inducers of transformed cell differentiation.Proc Natl Acad Sci 1996; 93: 5705–5708.

    Article  PubMed  Google Scholar 

  4. Zhou X, Marks PA, Rifkind RA, Richon VM. Cloning and haracterization of a histone deacetylase, HDAC9. Proc Natl Acad Sci 2001; 98: 10572–10577.

    Article  PubMed  Google Scholar 

  5. Minucci S, Nervi C, Lococo F, Pelicci PG. Histone deacetylases: A common molecular target for differentiation treatment of acute mycloid leukemias? Oncogene 2001; 20: 3110–3115.

    Article  PubMed  Google Scholar 

  6. Kelly WK, O'Connor OA, Marks PA. Histone deacetylase inhibitors: From target to clinical trials. Expert Opinion Invest Drugs 2002; 11: 1695–713.

    Google Scholar 

  7. DiLiberti JH, Farndon PA, Dennis NR, Curry CJ. The fetal valproate syndrome.Am J Med Genet 1984; 19: 473–481.

    PubMed  Google Scholar 

  8. Nau H, Hauck RS, Ehlers K. Valproic acid-induced neural tube defects in mouse and human: Aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacology Toxicol 1991; 9: 310–321.

    Google Scholar 

  9. Loscher W. Valproate: A reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 1999; 58: 31–59.

    Article  PubMed  Google Scholar 

  10. Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20: 6969–6978.

    Article  PubMed  Google Scholar 

  11. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer and teratogen. J Biol Chem 2001; 276: 36734–36741.

    Article  PubMed  Google Scholar 

  12. Warrel RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natlm Cancer Inst 1998; 90: 1621–1625.

    Article  Google Scholar 

  13. Lampen A, Siehler S, Ellerbeck U, Gottlicher M, Nau H. New molecular bioassays for the estimation of the teratogenic potency of valproic acid derivatives in vitro: Activation of the peroxisomal proliferator-activated receptor (PPARdelta). Toxicol Appl Pharmacol 1999; 160: 238–249.

    Article  PubMed  Google Scholar 

  14. Blaheta RA, Cinatl J Jr. Anti-tumor mechanisms of valproate: A novel role for an old drug. Medicinal Res Reviews 2002; 22: 492–511.

    Article  Google Scholar 

  15. Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to Apoptosis Vol 9 No 5 2004TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59: 2747–2753.

    PubMed  Google Scholar 

  16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265–275.

    PubMed  Google Scholar 

  17. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680–685.

    PubMed  Google Scholar 

  18. Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications.Proc Natl Ac Sci 1979; 76: 4350–4354.

    Google Scholar 

  19. Zhou Q, Fukushima P, DeGraff W, et al.Radiation and the Apo2L/TRAIL apoptotic pathway preferentially inhibit the colonization of premalignant human breast cells overexpressing cyclin D1. Cancer Res 2000; 60: 2611–2615.

    PubMed  Google Scholar 

  20. Falleni M, Pellegrini C, Marchetti A, et al.Survivin gene expression in early-stage non small cell lung cancer. J Pathology 2003; 200: 620–626.

    Article  Google Scholar 

  21. Jansson AJ, Emtering AM, Arbman G, Sun X. Noxa in colorectal cancer: A study on DNA, mRNA and protein expression. Oncogene 2003; 22: 675–678.

    Article  Google Scholar 

  22. Thome M, Schneider P, Hofmann K, et al.Viral FLICEinhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386: 517–521.

    Article  PubMed  Google Scholar 

  23. Cock JG, Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. CD95 (Fas/APO-1) induces ceramide formation and apoptosis in the absence of a functional acid sphingomyelinase. J Biol Chem 1998; 273: 7560–7565.

    Article  PubMed  Google Scholar 

  24. Cock JG, Jeanine GR, Tepper AD, de Vries E, van Blitterswilk WJ, Borst J. Common regulation of apoptosis signalling induced by CD95 and the DNA-damaging stimuli, etoposide and g-radiation downstream of caspase 3-activation. J Biol Chem 1999; 274: 14255–14261.

    Article  PubMed  Google Scholar 

  25. Hersey P, Zhang XD. How melanoma cells evade TRAILinduced apoptosis.Nature Reviews Cancer 2001; 1: 142–150.

    Article  PubMed  Google Scholar 

  26. La Porta CAM. Perspectives in melanoma treatment with signal transduction. Current Medicinal Chemistry-Anticancer Agents 2002; 3: 371–385.

    Google Scholar 

  27. Kawagoe R, Kawagoe H, Sano K. Valproic acid induces apoptosis in human leukemia cells by stimulating both caspasedependent and-independent apoptotic signaling pathways. Leukemia Res 2002; 26: 495–02.

    Article  Google Scholar 

  28. Ruvolo PP, Deng X, May WS. Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia 2001; 15: 515–522.

    Article  PubMed  Google Scholar 

  29. Myklebust JH, Josefsen D, Blomhoff HK, et al.Activation of the cAMP signalling pathway increases apoptosis in human Bprecursor cells and is associated with downregulation of Mcl-1 expression.J Cell Physiol 1999; 180: 71–80.

    Article  PubMed  Google Scholar 

  30. Townsend KJ, Zhou P, Qian L, et al.Regulation of MCL1 through a serum response factor/ELK-1 mediated mechanism links expression of a vciability-promoting member of the BCL2 family to the induction of ematopoietic cell differentiation. J Biol Chem 1999; 274: 1801–1813.

    Article  PubMed  Google Scholar 

  31. Selzer E, Schlagbauer-Wadl H, Okamoto I, Pehamberger H, Potter R, Jansen B. Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res 1998; 8: 197–203.

    PubMed  Google Scholar 

  32. PlettenbergA, Ballaun C, Pammer J, et al.Human melanocytes and melanoma cells constitutively express the Bcl-2 protooncogene in situ and in cell culture. Am J Pathol 1995; 146: 651–659.

    PubMed  Google Scholar 

  33. Selzer E, Hellinger C, Hoeller C, Oberkleiner P, Wacheck V, Pehemberger H, Jansen B. Betulimic acid-induced Mcl-1 expression in human melanoma made of action and functional significance. Mol Med 2002; 8: 877–884.

    PubMed  Google Scholar 

  34. Chen Y, Kramer DL, Li F, PorterCW. Loss of inhibitor of apoptosis proteins as a determinant of polyamine analog-induced apoptosis in human melanoma cells.Oncogene 2003; 22: 4964–4972.

    Article  PubMed  Google Scholar 

  35. Pennati M, Binda M, Colella G, et al.Radiosensitization of human melanoma cells by ribozyme-mediated inhibition of surviving expression. J Invest Dermatol 2003; 120: 648–654.

    PubMed  Google Scholar 

  36. Guo F, Sigua C, Tao J, et al.Cotreatment with Histone Deacetylase Inhibitor LAQ824 Enhances Apo-2L/Tumor Necrosis Factor-Related Apoptosis Inducing Ligand-Induced Death Inducing Signaling Complex Activity and Apoptosis of Human Acute Leukemia Cells. Cancer Res 2004; 64: 2580–2589.

    PubMed  Google Scholar 

  37. Gradilone A, Gazzaniga P, Ribuffo D, et al.Survivin, bcl-2, bax and bcl-X gene expression in sentinel lymph nodes from melanoma patients. J Clin Oncol 2003; 21: 306–312.

    Article  PubMed  Google Scholar 

  38. Grossman D, Kim PJ, Schechner JS, Altieri DC. Inhibition of melanoma tumor growth in vivoby surviving targeting. PNAS 2001; 98: 635–640.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomolecular Sciences and Biotechnology, University of Milan, Italy

    F. Facchetti, S. Previdi & C. A. M. La Porta

  2. European Institute of Oncology (IEO), Milan, Italy

    M. Ballarini

  3. Department of Biomolecular Sciences and Biotechnology, University of Milan, Italy

    S. Minucci

  4. European Institute of Oncology (IEO), Milan, Italy

    S. Minucci

  5. National Cancer Institute, Milan, Italy

    P. Perego

Authors
  1. F. Facchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Previdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Ballarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Minucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Perego
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. A. M. La Porta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. A. M. La Porta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Facchetti, F., Previdi, S., Ballarini, M. et al. Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors. Apoptosis 9, 573–582 (2004). https://doi.org/10.1023/B:APPT.0000038036.31271.50

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:APPT.0000038036.31271.50

Search

Navigation