Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo

Abstract

Proton radiation (PR) therapy offers a number of potential advantages over conventional (photon) γ-radiation (GR) therapy for cancer, due to a more localized delivery of the radiation dose. However, the pathophysiological effects following PR-exposure are less well characterized than those of GR-exposure and the molecular changes associated with the acute apoptotic effects in mice in vivo following PR have not been elucidated. Previous studies have estimated the RBE of protons for various in vivo and in vitro endpoints at between 1.1 and 1.3. We assumed an RBE of 1.1 for the endpoints to be evaluated in these studies. Based on this assumption, ICR mice were treated with whole-body doses of GR (1.1 and 7.0 Gy) and PR (1.0 and 6.4 Gy) that were expected to represent RBE-weighted doses. The bone marrow, thymus, spleen and GI-tract were isolated and processed for histology and immunohistochemistry. The apoptotic responses varied greatly between GR and PR in a tissue- and dose-dependent manner. Surprisingly, cell death in the splenic white pulp was consistently lower in PR-treated animals compared to animals treated with GR. This was in spite of an increased presence of damaged DNA following PR as determined by staining for γH2AX and phospho-ATM. Interestingly, both PR and GR triggered nuclear accumulation of p53 and no significant differences were found in the majority of the known pro-apoptotic p53-target genes in the spleens of treated mice. However, GR uniquely triggered a pro-apoptotic expression profile including expression of the pro-apoptotic, p53- and interferon stimulated target gene Bcl-G. In contrast to PR, GR may, in a cell type specific manner, trigger a more diverse non-random stress-response that mediates apoptosis partially independent of the extent of DNA damage.

Effect of proton and gamma irradiation on human lung carcinoma cells: Gene expression, cell cycle, cell death, epithelial–mesenchymal transition and cancer-stem cell trait as biological end points

“…This is the first study comparing the gene expression profiles in A549 cells after PI and GI, and highlights the quantitative differences in the numbers of altered genes. Consistent with previous reports [42], our data also revealed that many genes involved in cell cycle arrest and cell death were upregulated after GI and PI.…”

“…Pietro et al [47] demonstrated that compared with GI, PI significantly increased apoptosis in MCF7, PC3, and Ca3O1D cancer cell lines. In vivo, whole body irradiation studies by Finnberg et al demonstrated higher apoptosis by PI [42]. Our own data with A549 cells showed higher apoptosis at 72 h after PI, although till 48 hours, both GI and PI showed similar apoptosis, which could be due to higher cell cycle arrest after PI.…”

The effects of antioxidants on gene expression following gamma-radiation (GR) and proton radiation (PR) in mice in vivo

“…15 In a similar manner, we found that there was limited commonality between genes affected by AOX treatment following GR and PR. A reasonable assumption is that the minimal overlap in differentially expressed genes by AOX diet following GR and PR is a reflection of the vast qualitative gene expression differences between GR and PR, as previously shown.…”

“…GR triggered enriched changes in a more diverse set of signal transduction pathways compared with PR. 15 As part of this previously published study, we are examining the effect of AOX supplementation on gene expression changes occurring in the spleen of GR and PR irradiated mice in an attempt to generate further insight into the molecular mechanism of action of antioxidant diet in the context of radiation exposure. In concordance with the previous study, antioxidant dietary supplementation altered the expression pattern of pro-and anti-apoptotic gens, including many novel candidates potentially involved in the radiation response.…”

BCL2L14 (BCL2-like 14 (apoptosis facilitator))

“…BCL2L14 is itself a target gene for the apoptosis master regulator p53 (Miled et al, 2005), and it is one of a subset of proapoptotic genes whose expression is hyperactivated in response to interferon-α and -γ co-treatment of hepatoma cells (Zhang et al, 2006). Its expression is also increased in mammalian cells following exposure to a diverse range of apoptotic stimuli (including chemotherapeutic agents) such as: gamma-radiation therapy (Finnberg et al, 2008), UV-C irradiation (Pickard et al, 2011), arsenic trioxide (Galimberti et al, 2012), nanoparticulate tetraiodothyroacetic acid (Glinskii et al, 2009), etoposide and cisplatin (Benito et al, 2006). Mutations in pancreatic/duodenum homeobox protein 1 (PDX1) can result in human type 2 diabetes.…”