Overexpression of mitochondrial ferritin inhibited the tumour cell proliferation by regulation of cellular iron mechanism and the expression of cyclins

doi:10.3969/j.issn.0529-1356.2013.02.013

Abstract

Abstract:

Objective To study the mechanism of overexpression of mitochondrial ferritin(MtFt) for inhibiting neuroblastoma cell proliferation. Method MtFt-SY5Y cells were selected as the experimental model and SH-SY5Y and pcDNA3.1-SY5Y cells were used as control group. The effects of overexpression of MtFt on SH-SY5Y cells proliferation, iron metabolism related protein transferrin receptor1(TfR1) and ferritin, cyclins(cyclinD1, cyclinE ) and cyclin dependant kinases (CDK2, CDK4) were tested by flow cytometry and Western bloting. Result Overexpression of MtFt inhibited markedly tumour cell proliferation by regulation of iron metabolism and the expression of cyclins and cyclin dependant kinase. The proliferation speed of MtFt-SY5Y cells was 4 times slower than that of the control group. MtFt caused the cytoplasm iron deficiency and transferrin receptor1(TfR1) upregulation, and H-ferritin downregulation markedly respectively. Meanwhile, cyclinD1 and CDK2 downregulated significantly and cyclinE upregulated significantly. The expression of CDK4 decreased but no significant difference compared with control group. Conclusion Overexpression of MtFt inhibits the tumour cell proliferation markedly. The mechanism may be caused by regulation of cellular iron metabosism and the expression of cyclins and cyclin dependent kinase (CDK) which further arrest cell cycle.

Key words: Mitochondrial ferritin , Iron metabolism , Cell proliferation , Cyclin , Flow cytometry , Western blotting

CLC Number:

R739.4

SHI Fang-fang ZHANG Na GUAN Peng GAO Zhi-guo FAN Jing-qi CHANG Yan-zhong SHI Zhen-hua* DUAN Xiang-lin . Overexpression of mitochondrial ferritin inhibited the tumour cell proliferation by regulation of cellular iron mechanism and the expression of cyclins[J]. AAS, 2013, 44(2 ): 214-218.

References

［1］ Nurtjahja-Tjendraputra E, Fu D, Phang JM, et al. Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression［J］. Blood, 2007, 109(9): 4045-4054.

［2］ Krishnan K, Prathiba K, Jayaprakash V, et al. Synthesis and ribonucleotide reductase inhibitory activity of thiosemicarbazones［J］. Bioorg Med Chem Lett, 2008, 18(23): 6248-6250.

［3］ Huang X. Iron overload and its association with cancer risk in humans: evidence for iron as a carcinogenic metal［J］. Mutat Res, 2003, 533(12): 153-171.

［4］ Le NT, Richardson DR. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation［J］. Blood, 2004, 104(9): 2967-2975.

［5］ Rao VA, Zhang J, Klein SR, et al. The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats［J］. Cancer Chemother Pharmacol, 2011, 68(5): 1125-1134.

［6］ Gao J, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression［J］. Blood, 2001, 98(3): 842-850.

［7］ Lui GY, Obeidy P, Ford SJ, et al. The iron chelator, deferasirox, as a novel strategy for cancer Treatment: oral activity against human lung tumor xenografts and molecular mechanism of action［J］. Mol Pharmacol, 2013,83(1):179-190.

［8］ Snyder AM, Wang X, Patton SM, et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome［J］. J Neuropathol Exp Neurol, 2009, 68(11): 1193-1199.

［9］ Shi ZH, Nie G, Duan XL, et al. Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamineinduced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease［J］. Antioxid Redox Signal, 2010, 13(6): 783-796.

［10］Wu WS, Zhao YS, Shi ZH, et al. Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways［J］. Antioxid Redox Signal, 2013,18(2):158-169.

［11］Santambrogio P, Biasiotto G, Sanvito F, et al. Mitochondrial ferritin expression in adult mouse tissues［J］. J Histochem Cytochem, 2007, 55(11): 1129-1137.

［12］ Fukuchi K, Tomoyasu S, Watanabe H, et al. Iron deprivation results in an increase in p53 expression［J］. Biol Chem Hoppe Seyler, 1995, 376(10): 627-630.

［13］ Drysdale J, Arosio P, Invernizzi R, et al. Mitochondrial ferritin: a new player in iron metabolism［J］. Blood Cells Mol Dis, 2002, 29(3): 376-383.

［14］Noulsri E, Richardson DR, Lerdwana S, et al. Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells［J］. Am J Hematol, 2009, 84(3): 170-176.

［15］Wajapeyee N, Somasundaram K. Cell cycle arrest and apoptosis induction by activator protein 2alpha (AP-2alpha) and the role of p53 and p21WAF1/CIP1 in AP-2alpha-mediated growth inhibition［J］. J Biol Chem, 2003, 278(52): 52093-52101. 

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