With the construction of the Heavy Ion Mecial Machine (HIMM) in Wuwei, more and more work related to the research and development of heavy ion cancer therapy have been done in the group of Medical Physics this year. O...With the construction of the Heavy Ion Mecial Machine (HIMM) in Wuwei, more and more work related to the research and development of heavy ion cancer therapy have been done in the group of Medical Physics this year. On the one hand, we focused our work on setting up a heavy ion radiotherapy treatment planning system for the HIMM project, aiming at building a bridge between the HIMM facility and clinical application; on the other hand, we continued to explore the mechanisms underlying heavy ion radiation-induced biological effects in order to provide theoretical basis for heavy ion cancer therapy, trying either to improve the efficacy of heavy ion therapy or to reduce the radiation-induced damage to normal tissues as much as possible.展开更多
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair, and is also frequently over-expressed in tumor metastasis. We used isogenic cell lines expressing di...The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair, and is also frequently over-expressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. Interestingly, our results showed that X-ray irradiation induced the metastasis of DNA-PKcs positive (M059K) but not negative (M059J)cells; however, genistein could suppress the radiation-induced metastatic potential of M059K cells (Fig. 1). The concrete mechanisms underlying this phenomenon will be investigated next year.展开更多
Caspases as critical components in cell signaling pathways have been proved to be involved in events such asapoptosis, cell growth and differentiation. Two distinct apoptotic pathways related to the Caspase cascade ha...Caspases as critical components in cell signaling pathways have been proved to be involved in events such asapoptosis, cell growth and differentiation. Two distinct apoptotic pathways related to the Caspase cascade have beenidentified; death receptor-induced apoptosis and mitochondrial stress-induced apoptosis. Death receptors triggerCaspase-8 and the mitochondria subsequently release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading tothe activation of Caspase-9. The mitochondrial and death receptor apoptotic pathways are intimately connected[1].展开更多
Selectively killing cancer without harming normal tissue is a fundamental challenge in cancer therapy. Elevatedoxidative stress and aberrant redox homeostasis are frequently observed in cancer cells compared with thei...Selectively killing cancer without harming normal tissue is a fundamental challenge in cancer therapy. Elevatedoxidative stress and aberrant redox homeostasis are frequently observed in cancer cells compared with their normalcell counterparts[1]. A small shift toward an oxidizing condition in cells may lead to elevated proliferation andinduction of adaptive response. However, a high oxidizing condition often results in cell injury and cell death.Persistent high level of reactive oxygen species (ROS) in cancer cells usually elicits increased cell proliferation andadaptive responses that may contribute to tumorigenesis, metastasis, and treatment resistance. However, normalcells may still maintain redox homeostasis through adaptive responses. Therefore, regulating intracellular redoxstate may represent an ideal strategy to selectively sensitize cancer cells to oxidative stress-inducing therapy, suchas radiotherapy.展开更多
Migration and invasion are the integral process for cancer cell metastasis.X-ray irradiation could induce the invasion and migration of DNA-PKcs positive[Fig.1(b)]but not DNA-PKcs negative[Fig.1(a)]GBM cell lines,as s...Migration and invasion are the integral process for cancer cell metastasis.X-ray irradiation could induce the invasion and migration of DNA-PKcs positive[Fig.1(b)]but not DNA-PKcs negative[Fig.1(a)]GBM cell lines,as shown in Fig.1(c),(d)and(e).展开更多
DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a critical role in non-homologous end joining(NHEJ)of DNA double-stand break(DSB)repair.Previously,we found genistein could sensitize cancer cells to low l...DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a critical role in non-homologous end joining(NHEJ)of DNA double-stand break(DSB)repair.Previously,we found genistein could sensitize cancer cells to low linear energy transfer(LET)X-rays via inhibiting DNA-PKcs activities.Especially,high-LET heavy ion produces more DNA DSBs than low-LET radiation.Presently,we demonstrated that DNA-PKcs specific inhibitor Nu7026 treatment or siRNA knockdown of DNA-PKcs could sensitize DNA-PKcs proficient glioblastoma cells to high-LET carbon ions(shown in Table 1).Immunofluorescence and western blot experiments were performed to examine the DNA DSBs and their repair kinetics in two DNA-PKcs proficient glioblastoma cell lines.展开更多
The splicing of caspase-9 gene generates two isoforms such as caspase-9a and caspase-9b/9S,which can be generated by the inclusion or exclusion of a 4-exon cassette including exon 3,4,5,and 6 in the mature caspase-9 m...The splicing of caspase-9 gene generates two isoforms such as caspase-9a and caspase-9b/9S,which can be generated by the inclusion or exclusion of a 4-exon cassette including exon 3,4,5,and 6 in the mature caspase-9 mRNA[1].To investigate whether artificial increase of caspase-9a/9b mRNA ratio could enhance the sensitivity of non-small cell lung cancer(NSCLC)cells to low linear energy transfer(LET)X-rays and high-LET carbon ions,clonogenic survival assays were performed to detect the radiosensitivity of NSCLC A549 cells following caspase-9b knowdown and ionizing radiations.The results revealed that high-LET carbon ions enhanced the alternative splicingmediated radiosensitivity within the exposure dose limits,but low-LET X-rays could increase the radiosensitivity in a dose-dependent manner.展开更多
The previous studies have reported that DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a major role in radiosensitivity of cancer cells[1;2].We used colony formation assays to investigate the effects of...The previous studies have reported that DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a major role in radiosensitivity of cancer cells[1;2].We used colony formation assays to investigate the effects of genistein on isogenic cell lines expressing different levels of DNA-PKcs after exposure to heavy ions.As shown in Fig.1,genistein increased the radiosensitivity of DNA-PKcs positive(M059K)but not negative(M059J)glioma cells to heavy ions.To further determine whether sensitizing glioma cells to heavy ions by genistein is related to DNA-PKcs,we treated cells with Nu7026,a specific inhibitor of DNA-PK,and siRNA assays to interfere the expression of DNA-PKcs,both of which increased the radiosentivity of DNA-PKcs proficient cancer cells(M059K)as almost the same level as the genistein-treated group.展开更多
文摘With the construction of the Heavy Ion Mecial Machine (HIMM) in Wuwei, more and more work related to the research and development of heavy ion cancer therapy have been done in the group of Medical Physics this year. On the one hand, we focused our work on setting up a heavy ion radiotherapy treatment planning system for the HIMM project, aiming at building a bridge between the HIMM facility and clinical application; on the other hand, we continued to explore the mechanisms underlying heavy ion radiation-induced biological effects in order to provide theoretical basis for heavy ion cancer therapy, trying either to improve the efficacy of heavy ion therapy or to reduce the radiation-induced damage to normal tissues as much as possible.
文摘The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair, and is also frequently over-expressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. Interestingly, our results showed that X-ray irradiation induced the metastasis of DNA-PKcs positive (M059K) but not negative (M059J)cells; however, genistein could suppress the radiation-induced metastatic potential of M059K cells (Fig. 1). The concrete mechanisms underlying this phenomenon will be investigated next year.
文摘Caspases as critical components in cell signaling pathways have been proved to be involved in events such asapoptosis, cell growth and differentiation. Two distinct apoptotic pathways related to the Caspase cascade have beenidentified; death receptor-induced apoptosis and mitochondrial stress-induced apoptosis. Death receptors triggerCaspase-8 and the mitochondria subsequently release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading tothe activation of Caspase-9. The mitochondrial and death receptor apoptotic pathways are intimately connected[1].
文摘Selectively killing cancer without harming normal tissue is a fundamental challenge in cancer therapy. Elevatedoxidative stress and aberrant redox homeostasis are frequently observed in cancer cells compared with their normalcell counterparts[1]. A small shift toward an oxidizing condition in cells may lead to elevated proliferation andinduction of adaptive response. However, a high oxidizing condition often results in cell injury and cell death.Persistent high level of reactive oxygen species (ROS) in cancer cells usually elicits increased cell proliferation andadaptive responses that may contribute to tumorigenesis, metastasis, and treatment resistance. However, normalcells may still maintain redox homeostasis through adaptive responses. Therefore, regulating intracellular redoxstate may represent an ideal strategy to selectively sensitize cancer cells to oxidative stress-inducing therapy, suchas radiotherapy.
文摘Migration and invasion are the integral process for cancer cell metastasis.X-ray irradiation could induce the invasion and migration of DNA-PKcs positive[Fig.1(b)]but not DNA-PKcs negative[Fig.1(a)]GBM cell lines,as shown in Fig.1(c),(d)and(e).
文摘DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a critical role in non-homologous end joining(NHEJ)of DNA double-stand break(DSB)repair.Previously,we found genistein could sensitize cancer cells to low linear energy transfer(LET)X-rays via inhibiting DNA-PKcs activities.Especially,high-LET heavy ion produces more DNA DSBs than low-LET radiation.Presently,we demonstrated that DNA-PKcs specific inhibitor Nu7026 treatment or siRNA knockdown of DNA-PKcs could sensitize DNA-PKcs proficient glioblastoma cells to high-LET carbon ions(shown in Table 1).Immunofluorescence and western blot experiments were performed to examine the DNA DSBs and their repair kinetics in two DNA-PKcs proficient glioblastoma cell lines.
文摘The splicing of caspase-9 gene generates two isoforms such as caspase-9a and caspase-9b/9S,which can be generated by the inclusion or exclusion of a 4-exon cassette including exon 3,4,5,and 6 in the mature caspase-9 mRNA[1].To investigate whether artificial increase of caspase-9a/9b mRNA ratio could enhance the sensitivity of non-small cell lung cancer(NSCLC)cells to low linear energy transfer(LET)X-rays and high-LET carbon ions,clonogenic survival assays were performed to detect the radiosensitivity of NSCLC A549 cells following caspase-9b knowdown and ionizing radiations.The results revealed that high-LET carbon ions enhanced the alternative splicingmediated radiosensitivity within the exposure dose limits,but low-LET X-rays could increase the radiosensitivity in a dose-dependent manner.
文摘The previous studies have reported that DNA-dependent protein kinase catalytic subunit(DNA-PKcs)plays a major role in radiosensitivity of cancer cells[1;2].We used colony formation assays to investigate the effects of genistein on isogenic cell lines expressing different levels of DNA-PKcs after exposure to heavy ions.As shown in Fig.1,genistein increased the radiosensitivity of DNA-PKcs positive(M059K)but not negative(M059J)glioma cells to heavy ions.To further determine whether sensitizing glioma cells to heavy ions by genistein is related to DNA-PKcs,we treated cells with Nu7026,a specific inhibitor of DNA-PK,and siRNA assays to interfere the expression of DNA-PKcs,both of which increased the radiosentivity of DNA-PKcs proficient cancer cells(M059K)as almost the same level as the genistein-treated group.
