Mitoferrin-2-dependent mitochondrial iron uptake sensitizes human head and neck squamous carcinoma cells to photodynamic therapy

J Biol Chem. 2013 Jan 4;288(1):677-86. doi: 10.1074/jbc.M112.422667. Epub 2012 Nov 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / therapy
  • Cation Transport Proteins / metabolism*
  • Cell Line, Tumor
  • Chelating Agents / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / therapy
  • Humans
  • Iron / chemistry
  • Iron / metabolism*
  • Iron / pharmacokinetics*
  • Lysosomes / metabolism
  • Macrolides / pharmacology
  • Microscopy, Confocal / methods
  • Mitochondria / metabolism*
  • Models, Biological
  • Photochemotherapy / methods*
  • Reactive Oxygen Species
  • Time Factors

Substances

  • Cation Transport Proteins
  • Chelating Agents
  • Macrolides
  • Reactive Oxygen Species
  • SLC25A28 protein, human
  • bafilomycin A
  • Iron