Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair...Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2 AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation(radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to coadministration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA doublestrand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit(DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2 A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.展开更多
Incidences of head and neck squamous cell carcinoma(HNSCC)have been on the rise in the last few decades,with a significant risk factor being human papillomavirus(HPV)type-16/18 infection,particularly in the developmen...Incidences of head and neck squamous cell carcinoma(HNSCC)have been on the rise in the last few decades,with a significant risk factor being human papillomavirus(HPV)type-16/18 infection,particularly in the development of oropharyngeal cancers.Radiotherapy(RT)is an important treatment modality for HNSCC,where it promotes extensive cellular DNA damage leading to the therapeutic effect.It has been well-established that HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative HNSCC.The differential radiosensitivity has been largely associated with altered cellular DNA damage response mechanisms in HPV-positive HNSCC,and particularly with the signaling and repair of DNA double strand breaks.However,other factors,particularly hypoxia present within the solid cancer,have a major impact on relative radioresistance.Consequently,recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely centered on targeting key proteins involved in DNA repair,DNA damage checkpoint activation,and hypoxia signaling.These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC cell growth and survival.Here,accumulating evidence has shown that targeting enzymes including poly(ADP-ribose)polymerase,ataxia telangiectasia and Rad-3 related,DNA-dependent protein kinase catalytic subunit,and checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies,with the goal of optimizing the future effective RT treatment of HNSCC.展开更多
Radiotherapy can cause DNA damage into cells, triggering the cell cycle arrest and cell apop-tosis through complicated interactions among vital genes and their signal pathways. In order to in-depth study the complicat...Radiotherapy can cause DNA damage into cells, triggering the cell cycle arrest and cell apop-tosis through complicated interactions among vital genes and their signal pathways. In order to in-depth study the complicated cellular res- ponses under such a circumstance, a novel mo- del for P53 stress response networks is pro- posed. It can be successfully used to simulate the dynamic processes of DNA damage trans-ferring, ATM and ARF activation, regulations of P53-MDM2 feedback loop, as well as the toxins degradation. Particularly, it has become feasible to predict the outcomes of cellular response in fighting against genome stresses. Consequently, the new model has provided a reasonable framework for analyzing the complicated regu-lations of P53 stress response networks, as well as investigating the mechanisms of the cellular self-defense under radiotherapy.展开更多
Non-targeted effect is an important complement to the classical target theory of radiation biology which takesnuclear genomic DNA as the core target. The principle of radiation target theory is to assume that an organ...Non-targeted effect is an important complement to the classical target theory of radiation biology which takesnuclear genomic DNA as the core target. The principle of radiation target theory is to assume that an organism orcell has one or more sensitive points or targets, hit and inactivation of which directly by radiation leads toconsiderable damage and the death event. Recent findings indicate that not only cell nucleus but also othercellular parts can be considered as possible targets. Mitochondrion is considered as a critical organelle where thenon-targeted effect is initiated. A series of recent studies have provided substantial evidence and solid data whichprofoundly facilitate the understanding of radiation-induced non-targeted effects emitted from mitochondrion inthe irradiated cells, such the major apparent performances, signaling pathways and biological significance.Mitochondrial genome is more sensitive to genotoxic than nuclear genome. Ionizing radiation can induce mtDNAsdouble-strand breaks directly or indirectly via increased mitochondrial ROS. Under stress conditions, mitochondrial DNA (mtDNA) fragments are released into the cytoplasm. The cytosol mtDNAs are sensed by cGAS andAIM2 proteins and they activate the corresponding signaling pathways, generating relevant inflammatory andimmune responses. These newly developed mitochondrial DNA-initiating pathways may boost the development oftargeted therapies for preventing normal tissue toxicity as well as radio-immunotherapy, an emerging trend forcancer therapies. Here we focus and discuss the mechanisms and biological significance of mtDNA-triggeringcGAS/AIM2 signaling pathways of immune response from the aspect of non-targeted effect of radiation.展开更多
生长阻滞和DNA损伤基因45A(growth arrest and DNA damage-inducible 45A,GADD45A)是第1个被发现的由P53激活的应激诱导基因,同时也是P63、P73、BRCA1及MYC的靶标基因。GADD45A作为DNA损伤修复基因,受P53依赖(电离辐射诱导)和独立于P53...生长阻滞和DNA损伤基因45A(growth arrest and DNA damage-inducible 45A,GADD45A)是第1个被发现的由P53激活的应激诱导基因,同时也是P63、P73、BRCA1及MYC的靶标基因。GADD45A作为DNA损伤修复基因,受P53依赖(电离辐射诱导)和独立于P53(紫外线诱导)的途径调节,参与DNA损伤修复、细胞周期阻滞、凋亡、自噬、血管形成等生物学功能,与肿瘤发生发展密切相关。在大多数肿瘤的治疗中,化疗药物直接或者间接(如脱甲基化、乙酰化)上调其表达水平,提高癌细胞药物敏感性;同时,在放射治疗过程,过表达GADD45A可干预放射抵抗。然而,在少数肿瘤的治疗中,GADD45A的表达反而能够提高癌细胞的存活率。本文主要对GADD45A在肿瘤治疗中所发挥的作用及机制进行综述。展开更多
目的探讨miR-590-5p、DNA损伤检查点蛋白调节子1(mediator of DNA damage checkpoint 1,MDC1)在高级别胶质瘤(high-grade glioma,HGG)组织中的表达及与胶质瘤病人术后放疗效果的关系,并明确二者对胶质瘤细胞增殖、凋亡的影响。方法选取2...目的探讨miR-590-5p、DNA损伤检查点蛋白调节子1(mediator of DNA damage checkpoint 1,MDC1)在高级别胶质瘤(high-grade glioma,HGG)组织中的表达及与胶质瘤病人术后放疗效果的关系,并明确二者对胶质瘤细胞增殖、凋亡的影响。方法选取2019年1月至2021年2月河北北方学院附属第一医院64例HGG患者,评估放疗效果。实时荧光定量PCR(qRT-PCR)法检测miR-590-5p水平,免疫组织化学染色检测MDC1表达情况,分析miR-590-5p、MDC1表达与胶质瘤病人术后放疗效果的关系,多因素Logistic回归分析影响HGG患者术后放疗效果的因素;体外培养胶质瘤U87MG细胞,并分别转染miR-590-5p mimic、MDC1-shRNA及其阴性对照,CCK-8法和流式细胞术分别检测细胞增殖和凋亡;构建裸鼠移植瘤模型,观察过表达miR-590-5p和敲低MDC1对肿瘤生长的影响。结果MDC1在HGG组织中的表达较正常脑组织中升高,mi R-590-5p表达较正常脑组织降低,二者表达水平呈负相关;MDC1表达升高、miR-590-5p表达降低,其放疗效果越差;Logistic回归分析显示,MDC1高表达、miR-590-5p低表达均是影响HGG患者放疗效果的危险因素。过表达miR-590-5p和敲低MDC1后,U87MG细胞增殖力降低,凋亡率升高,移植瘤体积和重量下降,Ki-67阳性细胞比例减少。过表达miR-590-5p后MDC1蛋白表达明显下降。结论HGG组织中miR-590-5p呈低表达,MDC1呈高表达,二者表达与HGG的发生和患者术后放疗效果关系密切;过表达miR-590-5p和敲低MDC1表达可抑制胶质瘤细胞增殖并促进凋亡。展开更多
文摘Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2 AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation(radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to coadministration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA doublestrand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit(DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2 A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.
基金Fabbrizi MR and Parsons JL are supported by North West Cancer Research(No.CR1197).
文摘Incidences of head and neck squamous cell carcinoma(HNSCC)have been on the rise in the last few decades,with a significant risk factor being human papillomavirus(HPV)type-16/18 infection,particularly in the development of oropharyngeal cancers.Radiotherapy(RT)is an important treatment modality for HNSCC,where it promotes extensive cellular DNA damage leading to the therapeutic effect.It has been well-established that HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative HNSCC.The differential radiosensitivity has been largely associated with altered cellular DNA damage response mechanisms in HPV-positive HNSCC,and particularly with the signaling and repair of DNA double strand breaks.However,other factors,particularly hypoxia present within the solid cancer,have a major impact on relative radioresistance.Consequently,recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely centered on targeting key proteins involved in DNA repair,DNA damage checkpoint activation,and hypoxia signaling.These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC cell growth and survival.Here,accumulating evidence has shown that targeting enzymes including poly(ADP-ribose)polymerase,ataxia telangiectasia and Rad-3 related,DNA-dependent protein kinase catalytic subunit,and checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies,with the goal of optimizing the future effective RT treatment of HNSCC.
文摘Radiotherapy can cause DNA damage into cells, triggering the cell cycle arrest and cell apop-tosis through complicated interactions among vital genes and their signal pathways. In order to in-depth study the complicated cellular res- ponses under such a circumstance, a novel mo- del for P53 stress response networks is pro- posed. It can be successfully used to simulate the dynamic processes of DNA damage trans-ferring, ATM and ARF activation, regulations of P53-MDM2 feedback loop, as well as the toxins degradation. Particularly, it has become feasible to predict the outcomes of cellular response in fighting against genome stresses. Consequently, the new model has provided a reasonable framework for analyzing the complicated regu-lations of P53 stress response networks, as well as investigating the mechanisms of the cellular self-defense under radiotherapy.
基金This work was supported by grants from the National Natural Science Foundation of China(31870847).
文摘Non-targeted effect is an important complement to the classical target theory of radiation biology which takesnuclear genomic DNA as the core target. The principle of radiation target theory is to assume that an organism orcell has one or more sensitive points or targets, hit and inactivation of which directly by radiation leads toconsiderable damage and the death event. Recent findings indicate that not only cell nucleus but also othercellular parts can be considered as possible targets. Mitochondrion is considered as a critical organelle where thenon-targeted effect is initiated. A series of recent studies have provided substantial evidence and solid data whichprofoundly facilitate the understanding of radiation-induced non-targeted effects emitted from mitochondrion inthe irradiated cells, such the major apparent performances, signaling pathways and biological significance.Mitochondrial genome is more sensitive to genotoxic than nuclear genome. Ionizing radiation can induce mtDNAsdouble-strand breaks directly or indirectly via increased mitochondrial ROS. Under stress conditions, mitochondrial DNA (mtDNA) fragments are released into the cytoplasm. The cytosol mtDNAs are sensed by cGAS andAIM2 proteins and they activate the corresponding signaling pathways, generating relevant inflammatory andimmune responses. These newly developed mitochondrial DNA-initiating pathways may boost the development oftargeted therapies for preventing normal tissue toxicity as well as radio-immunotherapy, an emerging trend forcancer therapies. Here we focus and discuss the mechanisms and biological significance of mtDNA-triggeringcGAS/AIM2 signaling pathways of immune response from the aspect of non-targeted effect of radiation.
文摘生长阻滞和DNA损伤基因45A(growth arrest and DNA damage-inducible 45A,GADD45A)是第1个被发现的由P53激活的应激诱导基因,同时也是P63、P73、BRCA1及MYC的靶标基因。GADD45A作为DNA损伤修复基因,受P53依赖(电离辐射诱导)和独立于P53(紫外线诱导)的途径调节,参与DNA损伤修复、细胞周期阻滞、凋亡、自噬、血管形成等生物学功能,与肿瘤发生发展密切相关。在大多数肿瘤的治疗中,化疗药物直接或者间接(如脱甲基化、乙酰化)上调其表达水平,提高癌细胞药物敏感性;同时,在放射治疗过程,过表达GADD45A可干预放射抵抗。然而,在少数肿瘤的治疗中,GADD45A的表达反而能够提高癌细胞的存活率。本文主要对GADD45A在肿瘤治疗中所发挥的作用及机制进行综述。
文摘目的探讨miR-590-5p、DNA损伤检查点蛋白调节子1(mediator of DNA damage checkpoint 1,MDC1)在高级别胶质瘤(high-grade glioma,HGG)组织中的表达及与胶质瘤病人术后放疗效果的关系,并明确二者对胶质瘤细胞增殖、凋亡的影响。方法选取2019年1月至2021年2月河北北方学院附属第一医院64例HGG患者,评估放疗效果。实时荧光定量PCR(qRT-PCR)法检测miR-590-5p水平,免疫组织化学染色检测MDC1表达情况,分析miR-590-5p、MDC1表达与胶质瘤病人术后放疗效果的关系,多因素Logistic回归分析影响HGG患者术后放疗效果的因素;体外培养胶质瘤U87MG细胞,并分别转染miR-590-5p mimic、MDC1-shRNA及其阴性对照,CCK-8法和流式细胞术分别检测细胞增殖和凋亡;构建裸鼠移植瘤模型,观察过表达miR-590-5p和敲低MDC1对肿瘤生长的影响。结果MDC1在HGG组织中的表达较正常脑组织中升高,mi R-590-5p表达较正常脑组织降低,二者表达水平呈负相关;MDC1表达升高、miR-590-5p表达降低,其放疗效果越差;Logistic回归分析显示,MDC1高表达、miR-590-5p低表达均是影响HGG患者放疗效果的危险因素。过表达miR-590-5p和敲低MDC1后,U87MG细胞增殖力降低,凋亡率升高,移植瘤体积和重量下降,Ki-67阳性细胞比例减少。过表达miR-590-5p后MDC1蛋白表达明显下降。结论HGG组织中miR-590-5p呈低表达,MDC1呈高表达,二者表达与HGG的发生和患者术后放疗效果关系密切;过表达miR-590-5p和敲低MDC1表达可抑制胶质瘤细胞增殖并促进凋亡。
