Radiation Response Of Cancer Cells Research Articles

Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells.

Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F-cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line-specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078-87. ©2016 AACR.

Abstract 424: Depletion of serum levels of miRNA-150 indicates bone marrow damage following total body irradiation.

Abstract Total body irradiation (TBI) is part of the preparative regimen for bone marrow transplantation in lymphoma and leukemia patients. Depending on the aggressiveness of the disease, patients receive a dose between 2 -12 Gray, in 2 Gray fractions over three days. Fast and accurate estimation of the absorbed dose is critical for evaluation of the depletion of cancer cells prior to transplantation. Physical dosimeters and the available biologics have limitations to accurately evaluate the effect of radiation because the normal tissue toxicity as well as the radiation response in cancer cells varies depending on individual's genetics, immune status and other confounding factors. We sought to identify and validate robust and fast responding biomarkers of radiation response, which are repeatedly assayable from body fluids. We have utilized an amplification-free, hybridization based quantitative assay utilizing the nCounter multiplex platform developed by nanoString Technologies to compare the relative abundance of over 600 miRNAs in body fluids. Our studies have identified several evolutionarily and functionally conserved miRNAs in serum and urine collected from two different strains of mice. Development of a novel normalization strategy using multiple spike-in oligonucleotides allowed the accurate measurement of changes in serum and urine miRNAs after TBI. miRNAs with good dose response were further investigated for their potential for development as radiation biodosimeters. Hierarchical clustering followed by comparison of changes in individual miRNAs with varying dose (1 - 12 Gray) and time points (1 - 7 days) has identified miRNA-150 as a very promising biomarker for radiation biodosimetry. miRNA-150 is expressed at high level in mature lymphocytes and the abundance of circulating miRNA-150 seems correlating with that of lymphocyte counts. With acute single doses of 1, 2, 4, 6 and 8 Gray, a 30%, 38%, 48% 70% and 72% statistically significant reduction in serum miRNA-150 was observed at 24 hrs, which was further reduced at later time points. Consistent with this data, a time and dose dependent reduction of miRNA-150 was observed after fractionation, with a near complete depletion by 24 hrs after completion of 12 Gray. The kinetics of depletion of serum miRNA-150 following radiation indicate its potential as an alternative to complete blood count (CBC) to evaluate lymphocyte depletion, and hence evaluating damage to the hematopoietic system. The effect of relevant acute single doses and fractionated radiation treatment at various time points will be presented. The utilization of these readouts for understanding the effects and mechanism of action of radioprotectors will also be discussed. Citation Format: Naduparambil K. Jacob, James V. Cooley, Arnab Chakravarti. Depletion of serum levels of miRNA-150 indicates bone marrow damage following total body irradiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 424. doi:10.1158/1538-7445.AM2013-424

Guggulsterone-Mediated Enhancement of Radiosensitivity in Human Tumor Cell Lines

Purpose: To observe the effect of guggulsterone (GS) on the radiation response in human cancer cell lines. Materials and methods: The radiation response of cancer cells treated with GS was observed by cell survival studies, cell growth assay, NF-κB activity assay, western blotting of some key growth promoting receptors, the DNA repair protein γH2AX, and flow cytometry for DNA analyses. Results: GS inhibited radiation induced NF-κB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. It reduced both cell cycle movement and cell growth. GS reduced ERα protein in MCF7 cells and IGF1-Rβ protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. Conclusion: GS induced radiation sensitization may be due to several different mechanisms including the inhibition of NF-κB activation and reductions in IGF1-Rβ. In addition, GS induced γH2AX formation, primarily in the S-phase, indicates that DNA DSB's in the S-phase may be another reason for GS induced radiosensitivity. ERα down-regulation in response to GS suggests that it can be of potential use in the treatment of estrogen positive tumors that are resistant to tamoxifen.