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Metabolic reprogramming refers to the phenomenon that tumor cells, in order to meet their own growth and energy needs, regulate their biological functions by changing their metabolic mode, help themselves resist external stresses, and thus enable cells to adapt to hypoxia, acid, nutrient deficiency and other microenvironments and rapidly proliferate. It was found that metabolic reprogramming could contribute to radiation resistance and it also could be induced in bystander cells which may result in radiation resistance and the cancellation. Investigation the mechanism of radiation-induced metabolic reprogramming may provide new ideas and a theoretical framework for radiation protection, radiotherapy, and radio-diagnosis. This article reviewed the research progress on the mechanism of metabolic reprogramming in the direct and bystander effects of radiation.
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Radiation-induced bystander effect (RIBE) refers to that irradiated cells release signaling factors and induce responses in nonirradiated cells.In other words, it is the communication between irradiated and nonirradiated cells by intracellular signals. RIBE could influence the efficacy of tumor radiotherapy, but also has potential risk to the normal tissues outside of radiation field. Studies have found that ionizing radiation can induce the alteration of miRNA expression not only in the irradiated cells but also in adjacent nonirradiated tissues, and miRNAs may play an important role in the regulation of signaling pathways between irradiated and nonirradiated bystander cells. This article reviewed the roles of miRNAs in RIBE.
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Objective To investigate the role of ceramide in radiation induced bystander effect (RIBE) in vivo by irradiating Caenorhabditis elegans with proton microbeam.Methods The posterior pharynx of wide-type N2 and genetically mutated L4-staged worms was irradiated with 2 000 particles,then germ cell apoptosis and gene expression were analyzed.Results Point-fixed radiation to posterior pharynx of N2 worms significantly increased the number of apoptotic germ cells (t =9.007,P＜0.05),but not in the worms with deletion mutants of ceramide synthase (CerS) genes (hyl-1 and lagr-1) (P＞0.05).Realtime quantitative PCR assay indicated that in both N2 and lagr-1 (gk327);hyl-1 (ok976) worms,the genes of egl-1 and ced-13 in core apoptosis pathway were up-regulated after radiation to posterior pharynx,without statistical significance between these two strains (P＞0.05).The gene expression levels of hyl-1 and lagr-1 were increased in both N2 and hus-1 (op241) worms after radiation with no statistical significant difference between two strains (P＞0.05).Furthermore,radiation-induced germ cell apoptosis was increased in abl-1 (ok171) worms (t=13.241,P＜0.05),rather than in lagr-1(gk327);hyl-1(ok976);abl-1(ok171) worms (t=13.462,P＜0.05).Conclusions Ceramide is required for RIBE on germ cell apoptosis in C.elegans,and it might play function together with egl-1 and ced-13 in core apoptosis pathway and HUS-1 in DNA damage response pathway.But ceramide had antagonistic relationship with anti-apoptotic protein abl-1 in germ cell apoptosis.
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Objective To explore the influence of Guiqiyiyuan Ointment on the expressions of caspase-3 and caspase-9 in the lung and kidney of the rats damaged by heavy ion (12C6+) radiation-induced bystander effect.Methods The Wistar male rats were equally and randomly divided into seven groups,normal control group (NCG),radiation alone group (RAG) and Chinese medicine group (CMG),with the latter two groups being redivided into 6,12 and 24h groups according to the executing time.The Chinese medicine groups were given Guiqiyiyuan Ointment by gavage for two weeks in advance.The normal control group and the radiation alone groups were given the equal normal saline.Afterwards,the right lung of the rats in the radiation alone groups and Chinese medicine groups were radiated by 2Gy 12C6+ ion once.The rats in normal control group were not radiated.All groups of rats were executed 6,12,and 24h after radiation.The protein and mRNA expressions of caspase-3 and caspase-9 in the right lung,left lung and left kidney were examined with immunohistochemistry and Q-PCR.Results Compared with the normal control group,the mRNA expressions of caspase-3 and caspase-9 in the right lung,left lung and left kidney in the radiation alone groups obviously increased 6 and 24h after radiation.While the protein expressions of caspase-3 and caspase-9 in the radiation alone group obviously increased only 24h after radiation (P＜0.01).Compared with the radiation alone groups,the expressions of protein and mRNA ofcaspase-3 and caspase-9 were obviously down-regulated in the Chinese medicine groups (P＜0.01).Conclusion By controlling the up-regulation of the expression ofcaspase-3 and caspase-9,Guiqiyiyuan Ointment can prevent the lung and kidney cell apoptosis and alleviate the damage caused by heavy ion radiation-induced bystander effect in vivo.
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Objective To investigate the effect of SKP2 expression on radiation induced bystander effect (RIBE) of esophageal cancer cells.Methods The esophageal cancer cell lines with different SKP2 levels were applied for the study and the SKP2 expression was identified by Western blot.Micronuclei (MN) assay and DNA foci assay were used to evaluate the effect of SKP2 on RIBE.The cells were transfected with SKP2 gene or SKP2 siRNA to further verify the effect of SKP2 on RIBE.Results MN assay showed that the bystander effect induced by the cells with a high level of SKP2 was lower than that induced by the cells with a lower level of SKP2 (t =8.06,P ＜ 0.01).These results were further confirmed by the gene transfection experiments.When the expression of SKP2 was increased,RIBE was decreased (t=11.12,10.16,P ＜ 0.01).Contrarily,when the expression of SKP2 was reduced,RIBE was increased (t =8.39,8.83,P ＜ 0.01).γ-H2AX foci formation assay disclosed that when SKP2 expression in the irradiated cells increased,the repair ability of DNA damage in the bystander cells was higher than the control (t =6.85,7.10,P ＜ 0.01).With the expression of SKP2 decreased,the repair ability of DNA damage was lower than the control (t =7.66,8.47,P ＜ 0.01).Conclusions Over-expression of SKP2 inhibits RIBE of esophageal cancer cells,at least partly through regulating DNA damage repair ability.
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Objective To investigate radiation induced bystander effect and its mechanism on hepatoma HepG2 cells under hypoxia condition. Methods Non-irradiated bystander hepatoma cells were co-cultured with irradiated cells or treated with the conditioned medium (CM) from irradiated cells, then micronuclei (MN) were measured for both irradiated cells and bystander cells. Results The MN yield of irradiated HepG2 cells under hypoxic condition was significantly lower than that under normoxia, the oxygen enhancement ratio of HepG2 cells of MN was 1.6. For both hypoxic and normoxic condition, the MN yield of bystander cells were obviously enhanced to a similar high level after co-culturing with irradiated cells or with CM treatment, and it also correlated with the irradiation dose. When the hypoxic HepG2 cells were treated with either DMSO, a scavenger of reactive oxygen species (ROS), or aminognanidine, an iNOS inhibitor, the yield of bystander MN was partly diminished, and the reducing rate of DMSO was 42.2%-46.7 %, the reducing rate of aminognanidine was 42 %. Conclusion ROS, NO and their downstream signal facets are involved in the radiation induced bystander effect of hypoxic HepG2 cells.