title: Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy.
abstract: Photodynamic therapy (PDT) is a promising approach to treat head and neck cancer cells. Here, we investigated whether mitochondrial iron uptake through mitoferrin-2 (Mfrn2) enhanced PDT-induced cell killing. Three human head and neck squamous carcinoma cell lines (UMSCC1, UMSCC14A, and UMSCC22A) were exposed to light and Pc 4, a mitochondria-targeted photosensitizer. The three cell lines responded differently: UMSCC1 and UMSCC14A cells were more resistant, whereas UMSCC22A cells were more sensitive to Pc 4-PDT-induced cell death. In non-erythroid cells, Mfrn2 is an iron transporter in the mitochondrial inner membrane. PDT-sensitive cells expressed higher Mfrn2 mRNA and protein levels compared with PDT-resistant cells. High Mfrn2-expressing cells showed higher rates of mitochondrial Fe(2+) uptake compared with low Mfrn2-expressing cells. Bafilomycin, an inhibitor of the vacuolar proton pump of lysosomes and endosomes that causes lysosomal iron release to the cytosol, enhanced PDT-induced cell killing of both resistant and sensitive cells. Iron chelators and the inhibitor of the mitochondrial Ca(2+) (and Fe(2+)) uniporter, Ru360, protected against PDT plus bafilomycin toxicity. Knockdown of Mfrn2 in UMSCC22A cells decreased the rate of mitochondrial Fe(2+) uptake and delayed PDT plus bafilomycin-induced mitochondrial depolarization and cell killing. Taken together, the data suggest that lysosomal iron release and Mfrn2-dependent mitochondrial iron uptake act synergistically to induce PDT-mediated and iron-dependent mitochondrial dysfunction and subsequent cell killing. Furthermore, Mfrn2 represents a possible biomarker of sensitivity of head and neck cancers to cell killing after PDT.
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Hung
authors.forename: Justin M
authors.initials: JM
authors.lastname: Schwartz
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Maldonado
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Nieminen
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000628:therapy; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D008247:Lysosomes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010778:Photochemotherapy / Q000379:methods*; D017382:Reactive Oxygen Species; D013997:Time Factors
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D018942:Macrolides; D017382:Reactive Oxygen Species; C425684:SLC25A28 protein, human; C057620:bafilomycin A; D007501:Iron