Gene/Protein Disease Symptom Drug Enzyme Compound
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Chemerin exhibits a tumor-inhibitory role in hepatocellular carcinoma. However, the effect of chemerin on essential metal elements in hepatic cells remains unclear. In our study, the contents of six important metal ions, including potassium, calcium, sodium, magnesium, iron and zinc, were detected in human hepatoma SMMC7721 and immortal hepatic QSG7701 cells by ICP-AES. The data showed that chemerin only decreases the content of intracellular iron in SMMC7721 cells. The reduction was due to the blockage of iron entry through the decrease in the mRNA levels of divalent metal transporter 1, iron regulatory proteins and transferrin receptors. Furthermore, the reduction of the cellular iron content induced alterations of p53-p27-p21 signaling to arrest the cell cycle at S phase in SMMC7721 cells treated by chemerin. Conversely, iron addition led to recovery from the inhibitory effect of chemerin on SMMC7721 cells. The results suggest that chemerin plays an important role in inhibiting the cell proliferation of hepatocellular carcinomas by interfering with cellular iron homeostasis in this type of tumors.
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PMID:The involvement of iron in chemerin induced cell cycle arrest in human hepatic carcinoma SMMC7721 cells. 2987 20

Lipin1 participates in numerous cellular processes, including in the dephosphorylation of phosphatidic acid to diacylglycerol and as a co-transcriptional regulator. Iron is also essential in various critical biological processes. Previous studies have shown that compared to normal tissue cells, lipin1 expression and iron metabolism are abnormal in cancer cells. However, the involvement of lipin1 in the regulation of iron metabolism is unknown. In this study, we compared the contents of eight metal ions (potassium, calcium, sodium, magnesium, manganese, zinc, iron and copper) in human hepatoma carcinoma BEL7402 control cells as well as stable cells overexpressing lipin1 by using ICP-AES. Our results showed that only intracellular iron content was significantly decreased by lipin1 overexpression. Meanwhile, we observed that lipin1 overexpression could inhibit cell proliferation, similar to iron chelator deferoxamine. Western blotting showed that the up-regulation of p53-p21-p27 elicited cell cycle G0/G1 arrest in the stable cells overexpressing lipin1. Conversely, after lipin1 was down regulated with siRNA, we found that cell proliferation was promoted, accompanied by an increase in iron content, and the downregulation of p53 and p21. Our data indicate that lipin1 overexpression may cause reduction of intracellular iron content, which could activate the p53-p21-p27 signaling pathways, leading to cell cycle arrest at the G0/G1 phase in the hepatic carcinoma cells. Subsequently, we identified the putative cause for the decrease of the intracellular iron content induced by lipin1 overexpression. Our results suggested that the intracellular iron reduction was due to the increase in the expression of ferroportin, an iron export protein in the stable cells overexpressing lipin1. In contrast, after transfection with lipin1 siRNA, the decreased expression of ferroportin contributed to an increase in the iron content in BEL7402 cells. It was further confirmed that the intracellular iron content was increased after ferroportin was knocked down by siRNA in BEL7402 cells. Taken together, our findings demonstrate for the first time that lipin1 participates in the regulation of iron metabolism in human hepatic carcinoma cells. This suggests that lipin1 may play an important protective role in inhibiting the development of cancer through the reduction of iron content in tumors, which further demonstrates that iron reduction could be a potential strategy of cancer prevention and treatment.
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PMID:Iron depletion participates in the suppression of cell proliferation induced by lipin1 overexpression. 3014 7

Clioquinol is recently considered to be the most promising drug for treating cancer and neurodegenerative diseases. However, its mode of action varies from different disease models. In this study, we found that clioquinol inhibited cell growth in human neurotypic SHSY-5Y cells, which was attributed to both S-phase cell-cycle arrest and autophagic cell death. Clioquinol increased the intracellular contents of iron and zinc as well as calcium as measured by ICP-AES. Staining of Fluo-3 confirmed an increase in the level of calcium. Analysis of the metal-binding ability of clioquinol showed that it was not a chelating agent of calcium ions and the elevation of intracellular calcium content is not achieved by clioquinol as an ionophore. CaCl2 could simulate or even aggravate the cytotoxicity of clioquinol and it increased S-phase cell cycle arrest induced by clioquinol in a concentration dependent manner. Staining of acridine orange demonstrated that autophagy induced by clioquinol was not affected by addition of calcium ions. In contrast, the intracellular calcium ion chelator BAPTA-am abolished the clioquinol-induced S phase arrest and reduced the cell death caused by clioquinol. The WB assay of cell cycle-related proteins (CDK2, p21 and p27) further confirmed that S phase arrest is positively correlated with intracellular calcium elevation, which was due to the alterations of the mRNA and protein levels of calcium pumps (SERCA and SPCA). Taken together, these data indicate that clioquinol regulates the level of intracellular calcium ions to induce S-phase cell cycle arrest in human SH-SY5Y cells. Our results demonstrate for the first time that an increase of intracellular calcium content is one of the mechanisms of clioquinol in the inhibition of human neurotypic SHSY-5Y cells.
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PMID:Clioquinol induces S-phase cell cycle arrest through the elevation of the calcium level in human neurotypic SH-SY5Y cells. 3175 2