title: Mitochondrial ferritin, a new target for inhibiting neuronal tumor cell proliferation.
abstract: 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.
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang, 050024, Hebei, China, shizhhtom@126.com.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Shi
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Shi
authors.forename: Yue-Qi
authors.initials: YQ
authors.lastname: Wang
authors.forename: Alex D
authors.initials: AD
authors.lastname: Sheftel
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
authors.forename: Ya-Shuo
authors.initials: YS
authors.lastname: Zhao
authors.forename: Lin-Hao
authors.initials: LH
authors.lastname: You
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Gou
authors.forename: Xiang-Lin
authors.initials: XL
authors.lastname: Duan
authors.forename: Bao-Lu
authors.initials: BL
authors.lastname: Zhao
authors.forename: Hong-Meng
authors.initials: HM
authors.lastname: Xu
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Yan-Zhong
authors.initials: YZ
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D019938:Cyclin D1; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D005293:Ferritins; D047908:Intracellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000099259:N-myc Downstream-Regulated Gene 1 Protein