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.