title: Increased aldehyde reductase expression mediates acquired radioresistance of laryngeal cancer cells via modulating p53.
abstract: The main obstacle to cure tumors by radiotherapy has been ascribed to tumor radioresistance. To determine the mechanisms underlying resistance to irradiation, it is essential to compare proteins differentially expressed from radiotherapy-sensitive and -resistant cancer cells. Aldehyde reductase (AKR1A1) was recently identified as increased in radioresistant laryngeal cancer cells by comparative proteomics approach. Here, we provide the mechanism of AKR1A1-mediated radioresistance via p53 regulation in laryngeal cancer cells. AKR1A1 induction was correlated with the radioresistant phenotype of laryngeal cancer HEp-2 cells. AKR1A1 depletion with siRNA significantly enhanced radiation sensitivity of radioresistant HEp-2 cells by promoting radiation-induced cell death and accelerated radiation-mediated inhibition of cell proliferation, without affecting either the PI3K-Akt or MAPK-ERK pathways. Intriguingly, AKR1A1 depletion induced phosphorylation of p53 at serine 15 and G 2/M transition in response to irradiation. We further found that AKR1A1 interacted with p53 and this interaction was dramatically increased in the irradiated radioresistant cells compared with the control cells. AKR1A1 expression also regulated p53 stability in response to irradiation. Furthermore, AKR1A1 depletion only sensitized HCT116 cells expressing p53 to irradiation and not p53-deficient cells. Therefore, our data suggest that radiation-inducible AKR1A1 contributes to acquired radioresistance of laryngeal cancer cells by suppressing p53 activation through inhibitory interaction.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea. jaesung@kirams.re.kr
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Chang
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics*; D016923:Cell Death / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D000449:Aldehyde Reductase