Abstract
Some iron chelators display significant anticancer activity that may involve ferritin degradation either in proteasomes or in lysosomes, and the latter might involve ferritinophagy with a period. However, the correlation of ferritinophagy with anticancer activity of iron chelator was not fully determined. Revealing the underlying link therefore is required. Di-2-pyridylketone dithiocarbamate (DpdtC), a novel iron chelator, could mobilize iron from ferritin and displayed excellent antitumor against hepatoma carcinoma cell lines (IC50s = 0.4 ± 0.2 for HepG2 and 3.5 ± 0.3 μM for Bel-7402, resp.); we speculated that the antiproliferative action of DpdtC might involve ferritinophagy. To this end, the alterations of ferritin, microtubule-associated protein light chain 3 (LC3-II), and nuclear receptor coactivator 4 (NCOA4) were investigated after exposure of DpdtC to the cells. The results revealed that DpdtC could cause increases of autophagic vacuoles and LC3-II. The data from cellular immunofluorescence and Western blotting showed a reciprocal relation between abundances of ferritin and LC3-II, but the trends of NCOA4 and LC3-II in abundance were in a similar manner, indicating that a ferritinophagy occurred. Further studies revealed that the ferritinophagy evoked an iron-driven intralysosomal oxidative reaction, resulting in LMP change and lipid peroxidation. Thus, a ferritinophagy-mediated lysosomal ROS generation playing a role in the antiproliferative action of DpdtC could be proposed, which will enrich our knowledge of iron chelator in cancer therapy.
Highlights
Iron is an essential element and plays a crucial role in cellular proliferation and DNA synthesis
We presented a study of a novel iron chelator, Di-2-pyridylketone dithiocarbamate (DpdtC), on iron mobilization and proliferation, revealing that the occurrence of ferritinophagy was one of the crucial sources for reactive oxygen species (ROS) generation and partly contributed to its antitumor activity
We reported DpdtC having the ability in catalase inhibition that may partly contribute to the ROS production [19], which hinted that a Fenton reaction might occur, contributing its antiproliferative action
Summary
Iron is an essential element and plays a crucial role in cellular proliferation and DNA synthesis. It has been demonstrated that the LIP is regulated by ferritin, a highly conserved iron storage protein, which is composed of two subunits, H-ferritin and L-ferritin, and the twelve pairs of subunits binding head to foot form the 24-subunit ferritin cage [3, 4]. When the iron level in the cell is low, ferritin is degraded allowing the release of iron for use by the cell. Iron chelators lead to iron poor ferritins in vitro, there is no evidence that iron can exit ferritin prior to ferritin degradation in cellular level [6].
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