caa a22 4500 606176926 CHVBK 20210128100749.0 cr unu---uuuuu 210128e20150301xx s 000 0 eng 10.1007/s00018-014-1730-0 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1730-0 Mitochondrial ferritin, a new target for inhibiting neuronal tumor cell proliferation [Elektronische Daten] [Zhen-Hua Shi, Fang-Fang Shi, Yue-Qi Wang, Alex Sheftel, Guangjun Nie, Ya-Shuo Zhao, Lin-Hao You, Yu-Jing Gou, Xiang-Lin Duan, Bao-Lu Zhao, Hong-Meng Xu, Chun-Yan Li, Yan-Zhong Chang] 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. The Author(s), 2014 Neuroblastoma nationallicence Cyclin nationallicence Cell cycle nationallicence Cyclin-dependent protein kinase nationallicence Iron metabolism nationallicence Cdk : Cyclin-dependent protein kinase nationallicence CFSE : 5- or 6-(N-Succinimidyloxycarbonyl)-3′,6′-O,O'-diacetylfluorescein nationallicence FAC : Ammonium ferric citrate nationallicence FtMt : Mitochondrial ferritin nationallicence NB : Neuroblastoma nationallicence NBT : Normal brain tissue nationallicence NDRG1 : N-myc downstream-regulated gene-1 nationallicence NS : Neurospongioma nationallicence PCNA : Proliferating cell nuclear antigen nationallicence pRb : Phosphorylated retinoblastoma protein nationallicence Rb : Retinoblastoma protein nationallicence Shi Zhen-Hua Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Shi Fang-Fang Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Wang Yue-Qi Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Sheftel Alex University of Ottawa Heart Institute, 40 Ruskin St., K1Y 4W7, Ottawa, ON, Canada aut Nie Guangjun CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, 100190, Beijing, China aut Zhao Ya-Shuo Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut You Lin-Hao Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Gou Yu-Jing Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Duan Xiang-Lin Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Zhao Bao-Lu Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Xu Hong-Meng The Fourth Hospital of Hebei Medical University, 050011, Shijiazhuang, Hebei, China aut Li Chun-Yan The Second Hospital of Hebei Medical University, 050000, Shijiazhuang, Hebei, China aut Chang Yan-Zhong Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut Cellular and Molecular Life Sciences Springer Basel 72/5(2015-03-01), 983-997 1420-682X 72:5<983 2015 72 18 https://doi.org/10.1007/s00018-014-1730-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1730-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shi Zhen-Hua Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Shi Fang-Fang Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Wang Yue-Qi Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Sheftel Alex University of Ottawa Heart Institute, 40 Ruskin St., K1Y 4W7, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Nie Guangjun CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, 100190, Beijing, China aut NATIONALLICENCE 700 1- Zhao Ya-Shuo Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- You Lin-Hao Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Gou Yu-Jing Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Duan Xiang-Lin Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Zhao Bao-Lu Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Xu Hong-Meng The Fourth Hospital of Hebei Medical University, 050011, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Li Chun-Yan The Second Hospital of Hebei Medical University, 050000, Shijiazhuang, Hebei, China aut NATIONALLICENCE 700 1- Chang Yan-Zhong Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 050024, Shijiazhuang, Hebei, China aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/5(2015-03-01), 983-997 1420-682X 72:5<983 2015 72 18