title: Protein disulphide isomerase as a target for nanoparticle-mediated sensitisation of cancer cells to radiation.
abstract: Radiation resistance and toxicity in normal tissues are limiting factors in the efficacy of radiotherapy. Gold nanoparticles (GNPs) have been shown to be effective at enhancing radiation-induced cell death, and were initially proposed to physically enhance the radiation dose deposited. However, biological responses of GNP radiosensitization based on physical assumptions alone are not predictive of radiosensitisation and therefore there is a fundamental research need to determine biological mechanisms of response to GNPs alone and in combination with ionising radiation. This study aimed to identify novel mechanisms of cancer cell radiosensitisation through the use of GNPs, focusing on their ability to induce cellular oxidative stress and disrupt mitochondrial function. Using N-acetyl-cysteine, we found mitochondrial oxidation to be a key event prior to radiation for the radiosensitisation of cancer cells and suggests the overall cellular effects of GNP radiosensitisation are a result of their interaction with protein disulphide isomerase (PDI). This investigation identifies PDI and mitochondrial oxidation as novel targets for radiosensitisation.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, BT9 7AE, UK.
authors.forename: L E
authors.initials: LE
authors.lastname: Taggart
authors.forename: S J
authors.initials: SJ
authors.lastname: McMahon
authors.forename: K T
authors.initials: KT
authors.lastname: Butterworth
authors.forename: F J
authors.initials: FJ
authors.lastname: Currell
authors.forename: G
authors.initials: G
authors.lastname: Schettino
authors.forename: K M
authors.initials: KM
authors.lastname: Prise
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D053768:Metal Nanoparticles / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects / Q000528:radiation effects; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D018384:Oxidative Stress / Q000528:radiation effects; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D011838:Radiation-Sensitizing Agents; D006046:Gold; D019704:Protein Disulfide-Isomerases; D000111:Acetylcysteine