Mitochondrial ferritin, a new target for inhibiting neuronal tumor cell proliferation

Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels. However, because of the deficiency of iron regulatory elements (IRE) in FtMt’s gene sequence, the exact function of FtMt remains unclear. In the present study, we found that FtMt dram...

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Published in:Cellular and molecular life sciences : CMLS 2015-03, Vol.72 (5), p.983-997
Main Authors: Shi, Zhen-Hua, Shi, Fang-Fang, Wang, Yue-Qi, Sheftel, Alex D, Nie, Guangjun, Zhao, Ya-Shuo, You, Lin-Hao, Gou, Yu-Jing, Duan, Xiang-Lin, Zhao, Bao-Lu, Xu, Hong-Meng, Li, Chun-Yan, Chang, Yan-Zhong
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biochemistry
Biomedical and Life Sciences
Biomedicine
brain
Cell Biology
Cell cycle
Cell Cycle Proteins - metabolism
Cell growth
Cell Line, Tumor
Cell Proliferation
Cyclin D1 - metabolism
Cyclin E - metabolism
cyclin-dependent kinase
Cyclin-Dependent Kinase 2 - metabolism
Cyclin-dependent kinases
Drosophila
ferritin
Ferritins - genetics
Ferritins - metabolism
G1 Phase Cell Cycle Checkpoints
gene expression regulation
gene overexpression
homeostasis
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Iron
Life Sciences
Male
Metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Mitochondria
Mitochondria - metabolism
neoplasm cells
Neuroblastoma - metabolism
Neuroblastoma - pathology
nucleotide sequences
proliferating cell nuclear antigen
Proto-Oncogene Proteins c-myc - metabolism
Research Article
Retinoblastoma Protein - metabolism
therapeutics
transferrin
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary:Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels. However, because of the deficiency of iron regulatory elements (IRE) in FtMt’s gene sequence, the exact function of FtMt remains unclear. In the present study, we found that FtMt dramatically inhibited SH-SY5Y cell proliferation and tumor growth in nude mice. Interestingly, excess FtMt did not adversely affect the development of drosophila. Additionally, we found that the expression of FtMt in human normal brain tissue was significantly higher than that of neuroblastoma, but not higher than that of neurospongioma. However, the expression of transferrin receptor 1 is completely opposite. We therefore hypothesized that increased expression of FtMt may negatively affect the vitality of neuronal tumor cells. Therefore, we further investigated the underlying mechanisms of FtMt’s inhibitory effects on neuronal tumor cell proliferation. As expected, FtMt overexpression disturbed the iron homeostasis of tumor cells and significantly downregulated the expression of proliferating cell nuclear antigen. Moreover, FtMt affected cell cycle, causing G1/S arrest by modifying the expression of cyclinD1, cyclinE, Cdk2, Cdk4 and p21. Remarkably, FtMt strongly upregulated the expression of the tumor suppressors, p53 and N-myc downstream-regulated gene-1 (NDRG1), but dramatically decreased C-myc, N-myc and p-Rb levels. This study demonstrates for the first time a new role and mechanism for FtMt in the regulation of cell cycle. We thus propose FtMt as a new candidate target for inhibiting neuronal tumor cell proliferation. Appropriate regulation of FtMt expression may prevent tumor cell growth. Our study may provide a new strategy for neuronal cancer therapy.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-014-1730-0