Abstract
In recent years, increasing evidence indicated the importance of a deregulated c-myc gene in the melanoma pathogenesis. We have previously demonstrated that treatment of melanoma cells with c-myc antisense oligodeoxynucleotides can inhibit cell proliferation and activate apoptosis. To gain insight into the mechanisms activated by Myc down-regulation, we have now developed an experimental model that allows modulating Myc protein expression in melanoma cells. This was achieved by originating stable melanoma cell clones expressing ecdysone-inducible c-myc antisense RNA. We show that the induction of c-myc antisense RNA in M14 melanoma cells leads to an inhibition of cell proliferation characterized by accumulation of cells in the G1 phase of the cell cycle (up to 80%) and activation of apoptosis (50%). These data are associated with an increase of p27kip1 levels and a significant reduction of the cdk2-associated kinase activity. In addition, we show that an ectopic overexpression of p27kip1 in this experimental model can enhance the apoptotic rate. Our results indicate that down-regulation of Myc protein induces a G1 arrest and activates apoptosis by increasing p27kip1 content in melanoma cells, that are known to be defective for the p16-cyclinD/cdk4-pRb G1 checkpoint. This is particularly relevant for identifying new therapeutic strategies based on the re-establishment of the apoptotic pathways in cancer cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J, Bartek J . 1996 Cancer Res. 56: 5475–5483
Burgess TL, Fisher EF, Ross SL, Bready JV, Qian YX, Bayewitch LA, Cohen AM, Herrera CJ, Hu SS, Kramer TB . 1995 Proc. Natl. Acad. Sci. USA 92: 4051–4055
Castellano M, Parmiani G . 1999 Melanoma Res. 9: 421–432
Citro G, D'Agnano I, Leonetti C, Perini R, Bucci B, Zon G, Calabretta B, Zupi G . 1998 Cancer Res. 58: 283–289
Crooke ST . 1996 Antisense Nucleic Acid Drug Dev. 6: 145–147
D'Agnano I, Antonelli A, Bucci B, Marcucci L, Petrinelli P, Ambra R, Zupi G, Elli R . 1998 Environ. Mol. Mutagen. 32: 56–63
Daksis JI, Lu RY, Facchini LM, Marhin WW, Penn LJ . 1994 Oncogene 9: 3635–3645
Dang CV . 1999 Mol. Cell Biol. 19: 1–11
Evan G, Littlewood T . 1998 Science 281: 1317–1322
Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC . 1992 Cell 69: 119–128
Ezhevsky SA, Toyoshima H, Hunter T, Scott DW . 1996 Mol. Biol. Cell 7: 553–564
Fischer G, Kent SC, Joseph L, Green DR, Scott DW . 1994 J. Exp. Med. 179: 221–228
Hanson KD, Shichiri M, Follansbee MR, Sedivy JM . 1994 Mol. Cell Biol. 14: 5748–5755
Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV . 1994 Proc. Natl. Acad. Sci. USA 91: 6875–6879
Jansen-Durr P, Meichle A, Steiner P, Pagano M, Finke K, Botz J, Wessbecher J, Draetta G, Eilers M . 1993 Proc. Natl. Acad. Sci. USA 90: 3685–3689
Kalejta RF, Shenk T, Beavis AJ . 1997 Cytometry 29: 286–291
Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P . 1997 Cancer Res. 57: 5441–5445
Kimura S, Maekawa T, Hirakawa K, Murakami A, Abe T . 1995 Cancer Res. 55: 1379–1384
Krieg AM, Stein CA . 1995 Antisense Res. Dev. 5: 241
Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR . 1997 Nature 387: 422–426
Leonetti C, D'Agnano I, Lozupone F, Valentini A, Geiser T, Zon G, Calabretta B, Citro GC, Zupi G . 1996 J. Natl. Cancer Inst. 88: 419–429
Lesnikowski ZJ, Jaworska M, Stec WJ . 1990 Nucleic Acids Res. 18: 2109–2115
Maelandsmo GM, Florenes VA, Hovig E, Oyjord T, Engebraaten O, Holm R, Borresen AL, Fodstad O . 1996 Br. J. Cancer 73: 909–916
Mateyak MK, Obaya AJ, Sedivy JM . 1999 Mol. Cell Biol. 19: 4672–4683
O'Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin Jr WG, DePinho RA . 2000 Genes Dev. 14: 2185–2191
Obaya AJ, Mateyak MK, Sedivy JM . 1999 Oncogene 18: 2934–2941
Perez-Roger I, Solomon DL, Sewing A, Land H . 1997 Oncogene 14: 2373–2381
Ross DA, Wilson GD . 1998 Br. J. Surg. 85: 46–51
Ryan KM, Birnie GD . 1996 Biochem. J. 314: 713–721
Schlagbauer-Wadl H, Griffioen M, van Elsas A, Schrier PI, Pustelnik T, Eichler HG, Wolff K, Pehamberger H, Jansen B . 1999 J. Invest. Dermatol. 112: 332–336
Schmidt EV . 1999 Oncogene 18: 2988–2996
Schraml P, Kononen J, Bubendorf L, Moch H, Bissig H, Nocito A, Mihatsch MJ, Kallioniemi OP, Sauter G . 1999 Clin. Cancer Res. 5: 1966–1975
Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE . 1997 Genes Dev. 11: 1464–1478
Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR . 1992 Science 257: 212–214
Skorski T, Nieborowska-Skorska M, Campbell K, Iozzo RV, Zon G, Darzynkiewicz Z, Calabretta B . 1995 J. Exp. Med. 182: 1645–1653
Stein CA . 1996 J. Natl. Cancer Inst. 88: 391–393
Stein CA . 1998 Antisense Nucleic Acid Drug Dev. 8: 129–132
Van den Heuvel S, Harlow E . 1993 Science 262: 2050–2054
van Waardenburg RC, Meijer C, Burger H, Nooter K, de Vries EG, Mulder NH, De Jong S . 1997 Int. J. Cancer 73: 544–550
Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B . 1996 EMBO J. 15: 6595–6604
Vlach J, Hennecke S, Amati B . 1997 EMBO J. 16: 5334–5344
Wang X, Gorospe M, Huang Y, Holbrook NJ . 1997 Oncogene 15: 2991–2997
Wu M, Bellas RE, Shen J, Yang W, Sonenshein GE . 1999 J. Immunol. 163: 6530–6535
Acknowledgements
We thank Maurizia Caruso for critically reading the manuscript; and Alessandra Rinaldi for technical assistance. This work was supported by grants from CNR, Target Project on Biotechnology (to I D'Agnano) and Progetto Strategico ‘Oncologia’ MURST-CNR (to A Felsani).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
D'Agnano, I., Valentini, A., Fornari, C. et al. Myc down-regulation induces apoptosis in M14 melanoma cells by increasing p27kip1 levels. Oncogene 20, 2814–2825 (2001). https://doi.org/10.1038/sj.onc.1204392
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204392
Keywords
This article is cited by
-
E2F1-induced lncRNA, EMSLR regulates lncRNA LncPRESS1
Scientific Reports (2022)
-
FBX8 promotes metastatic dormancy of colorectal cancer in liver
Cell Death & Disease (2020)
-
c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle
Oncogene (2008)
-
Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes
Oncogene (2005)
-
Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions
Modern Pathology (2004)