Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells

Christopher J. Wallick, Ivonne Gamper, Mike Thorne, David J. Feith, Kelsie Y. Takasaki, Shannon M. Wilson, Jennifer A. Seki, Anthony E. Pegg, Craig V. Byus, André S. Bachmann

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Abstract

Alpha-difluoromethylornithine (DFMO) inhibits the protooncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G 1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.

Original languageEnglish (US)
Pages (from-to)5606-5618
Number of pages13
JournalOncogene
Volume24
Issue number36
DOIs
StatePublished - Aug 25 2005

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Cyclin-Dependent Kinase Inhibitor p27
Eflornithine
4-amidinoindan-1-one 2'-amidinohydrazone
G1 Phase Cell Cycle Checkpoints
Retinoblastoma Protein
Polyamines
Neuroblastoma
Cell Cycle Checkpoints
Adenosylmethionine Decarboxylase
Local Area Networks
Cell Line
Gastrin-Secreting Cells
Ornithine Decarboxylase
Cyclin-Dependent Kinases
Cell Death
Phosphorylation
Apoptosis
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Wallick, C. J., Gamper, I., Thorne, M., Feith, D. J., Takasaki, K. Y., Wilson, S. M., ... Bachmann, A. S. (2005). Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells. Oncogene, 24(36), 5606-5618. https://doi.org/10.1038/sj.onc.1208808
Wallick, Christopher J. ; Gamper, Ivonne ; Thorne, Mike ; Feith, David J. ; Takasaki, Kelsie Y. ; Wilson, Shannon M. ; Seki, Jennifer A. ; Pegg, Anthony E. ; Byus, Craig V. ; Bachmann, André S. / Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells. In: Oncogene. 2005 ; Vol. 24, No. 36. pp. 5606-5618.
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abstract = "Alpha-difluoromethylornithine (DFMO) inhibits the protooncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G 1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.",
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Wallick, CJ, Gamper, I, Thorne, M, Feith, DJ, Takasaki, KY, Wilson, SM, Seki, JA, Pegg, AE, Byus, CV & Bachmann, AS 2005, 'Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells', Oncogene, vol. 24, no. 36, pp. 5606-5618. https://doi.org/10.1038/sj.onc.1208808

Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells. / Wallick, Christopher J.; Gamper, Ivonne; Thorne, Mike; Feith, David J.; Takasaki, Kelsie Y.; Wilson, Shannon M.; Seki, Jennifer A.; Pegg, Anthony E.; Byus, Craig V.; Bachmann, André S.

In: Oncogene, Vol. 24, No. 36, 25.08.2005, p. 5606-5618.

Research output: Contribution to journalArticle

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T1 - Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells

AU - Wallick, Christopher J.

AU - Gamper, Ivonne

AU - Thorne, Mike

AU - Feith, David J.

AU - Takasaki, Kelsie Y.

AU - Wilson, Shannon M.

AU - Seki, Jennifer A.

AU - Pegg, Anthony E.

AU - Byus, Craig V.

AU - Bachmann, André S.

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Y1 - 2005/8/25

N2 - Alpha-difluoromethylornithine (DFMO) inhibits the protooncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G 1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.

AB - Alpha-difluoromethylornithine (DFMO) inhibits the protooncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G 1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.

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