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Deoxyhypusine synthase (DHPS) inhibitor GC7 induces p21/Rb-mediated inhibition of tumor cell growth and DHPS expression correlates with poor prognosis in neuroblastoma patients
- Source :
- Cellular oncology (Dordrecht), 37(6), 387-398. IOS Press, Cellular Oncology, 37(6), 387-98. IOS Press, Bandino, A, Geerts, D, Koster, J & Bachmann, A S 2014, ' Deoxyhypusine synthase (DHPS) inhibitor GC7 induces p21/Rb-mediated inhibition of tumor cell growth and DHPS expression correlates with poor prognosis in neuroblastoma patients ', Cellular Oncology, vol. 37, no. 6, pp. 387-98 . https://doi.org/10.1007/s13402-014-0201-9
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- PURPOSE: Neuroblastoma (NB) is an aggressive pediatric malignancy that typically occurs in infants and children under the age of 5 years. High-stage tumors relapse frequently even after aggressive multimodal treatment, resulting in therapy resistance and eventually in patient death. Clearly, new biologically-targeted drugs are needed that more efficiently suppress tumor growth and prevent relapse. We and others previously showed that polyamines such as spermidine play an essential role in NB tumorigenesis and that DFMO, an inhibitor of the central polyamine synthesis gene ODC, is effective in vitro and in vivo, prompting its evaluation in NB clinical trials. However, the specific molecular actions of polyamines remain poorly defined. Spermidine and deoxyhypusine synthase (DHPS) are essential components in the hypusination-driven post-translational activation of eukaryotic initiation factor 5A (eIF5A).METHODS: We assessed the role of DHPS in NB and the impact of its inhibition by N(1)-guanyl-1,7-diaminoheptane (GC7) on tumor cell growth using cell proliferation assays, Western blot, immunofluorescence microscopy, and Affymetrix micro-array mRNA expression analyses in NB tumor samples.RESULTS: We found that GC7 inhibits NB cell proliferation in a dose-dependent manner, through induction of the cell cycle inhibitor p21 and reduction of total and phosphorylated Rb proteins. Strikingly, high DHPS mRNA expression correlated significantly with unfavorable clinical parameters, including poor patient survival, in a cohort of 88 NB tumors (all P CONCLUSIONS: These results suggest that spermidine and DHPS are key contributing factors in NB tumor proliferation through regulation of the p21/Rb signaling axis.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Cancer Research
Guanine
Blotting, Western
Antineoplastic Agents
DHPS
medicine.disease_cause
Retinoblastoma Protein
Neuroblastoma
chemistry.chemical_compound
Cell Line, Tumor
medicine
Humans
Deoxyhypusine synthase
Cell Proliferation
Oligonucleotide Array Sequence Analysis
Oxidoreductases Acting on CH-NH Group Donors
biology
Cell growth
General Medicine
Cell cycle
Prognosis
medicine.disease
Spermidine
Microscopy, Fluorescence
Oncology
chemistry
biology.protein
Cancer research
Molecular Medicine
Carcinogenesis
EIF5A
Subjects
Details
- ISSN :
- 22113436, 22113428, and 18758606
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Cellular Oncology
- Accession number :
- edsair.doi.dedup.....1914a4989f7fee8544ffa4dd4f885c08
- Full Text :
- https://doi.org/10.1007/s13402-014-0201-9