LCN2-Fungal siderophore-iron binding and uptake leads to oxidative stress and cell death in hepatocellular carcinoma cell line HepG2

Microorganisms produce non-ribosomal peptides called siderophores for the purpose of iron acquisition. Mammalian immune system is well-known for producing small secretory proteins called lipocalins upon bacterial infection. These proteins sequester siderophores produced by invading bacterial pathogens rendering them unable to acquire iron from the host. However, this is not their sole function. In addition to transferrin and lactoferrin, lipocalins are also known to transport siderophore-bound iron to the host cells. While binding of bacterial siderophores with human lipocalin is well studied, binding of the fungal counterpart is still not confirmed and fully understood. Apart from pathogen-affected cells, developing cancerous cells also show varying expression level of different proteins including those involved in iron transport. The possibility of exogenous fungal siderophore-mediated iron transport via lipocalin and its receptor in mammalian cells has not yet been explored much. In present investigation we have checked differential expression of human lipocalin, LCN2 in hepatocellular carcinoma cell lines HepG2 as well as its normal counterpart WRL-68 and computationally determined the feasibility of LCN2 binding with fungal siderophore. Further in case of a stable complex being formed, whether this complex has the ability to transport iron through its specific receptor was assessed. Also, we have tried to explore possible mechanism of fungal-siderophore mediated oxidative stress leading to significant cell death in cancerous cells. This study will thus be useful towards finding a new way of treating hepatocellular carcinoma via inducing siderophore-mediated cell death in cancerous cells.Communicated by Ramaswamy H. Sarma

Automated summary

Microorganisms produce siderophores to acquire iron, while the mammalian immune system produces lipocalins to sequester these siderophores from invading bacterial pathogens. Lipocalins can also transport siderophore-bound iron to host cells. However, the binding of fungal siderophores with human lipocalins is still not fully understood. This study investigates the expression of human lipocalin and its binding with fungal siderophore, as well as the potential mechanism of siderophore-mediated cell death in hepatocellular carcinoma.