title: Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin.
abstract: Artesunate (ART) is an anti-malaria drug that has been shown to exhibit anti-tumor activity, and functional lysosomes are reported to be required for ART-induced cancer cell death, whereas the underlying molecular mechanisms remain largely elusive. In this study, we aimed to elucidate the molecular mechanisms underlying ART-induced cell death. We first confirmed that ART induces apoptotic cell death in cancer cells. Interestingly, we found that ART preferably accumulates in the lysosomes and is able to activate lysosomal function via promotion of lysosomal V-ATPase assembly. Furthermore, we found that lysosomes function upstream of mitochondria in reactive oxygen species production. Importantly, we provided evidence showing that lysosomal iron is required for the lysosomal activation and mitochondrial reactive oxygen species production induced by ART. Finally, we showed that ART-induced cell death is mediated by the release of iron in the lysosomes, which results from the lysosomal degradation of ferritin, an iron storage protein. Meanwhile, overexpression of ferritin heavy chain significantly protected cells from ART-induced cell death. In addition, knockdown of nuclear receptor coactivator 4, the adaptor protein for ferritin degradation, was able to block ART-mediated ferritin degradation and rescue the ART-induced cell death. In summary, our study demonstrates that ART treatment activates lysosomal function and then promotes ferritin degradation, subsequently leading to the increase of lysosomal iron that is utilized by ART for its cytotoxic effect on cancer cells. Thus, our data reveal a new mechanistic action underlying ART-induced cell death in cancer cells.
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine.
authors.forename: Nai-Di
authors.initials: ND
authors.lastname: Yang
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine, the NUS Graduate School for Integrative Sciences and Engineering.
authors.forename: Shi-Hao
authors.initials: SH
authors.lastname: Tan
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine.
authors.forename: Shukie
authors.initials: S
authors.lastname: Ng
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine.
authors.forename: Yin
authors.initials: Y
authors.lastname: Shi
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: the Department of Microbiology, Yong Loo Lin School of Medicine.
authors.forename: Kevin Shyong Wei
authors.initials: KS
authors.lastname: Tan
authors.affiliation: the Department of Pharmacology, Yong Loo Lin School of Medicine, and.
authors.forename: Wai-Shiu Fred
authors.initials: WS
authors.lastname: Wong
authors.affiliation: From the Department of Physiology, Yong Loo Lin School of Medicine, the NUS Graduate School for Integrative Sciences and Engineering, the Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore han-ming_shen@nuhs.edu.sg.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D016923:Cell Death / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C111382:NCOA4 protein, human; D009363:Neoplasm Proteins; D056918:Nuclear Receptor Coactivators; D000077332:Artesunate; D005293:Ferritins; D007501:Iron; D025262:Vacuolar Proton-Translocating ATPases
keywords: Artesunate; Cell Death; Ferritin; Iron; Lysosome; Reactive Oxygen Species (ROS)