MP-04.01: Molecular mechanisms of the urinary bladder carcinogenesis (the intercellular proteolysis alteration) influenced by persistent, long-term, low-dose ionizing radiation in humans

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

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Induction of Hematopoietic Stem Cell Senescence by Ionizing Radiation.

Blood ◽

10.1182/blood.v106.11.1362.1362 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1362-1362

Author(s):

Yong Wang ◽

Bradley A. Schulte ◽

Amanda C. LaRue ◽

Makio Ogawa ◽

Daohong Zhou

Keyword(s):

Stem Cell ◽

Ionizing Radiation ◽

Hematopoietic Stem Cell ◽

Cellular Senescence ◽

Molecular Mechanisms ◽

Chemotherapeutic Agents ◽

Sublethal Dose ◽

Self Renewal ◽

Hematopoietic Stem

Abstract Exposure to ionizing radiation (IR) and certain chemotherapeutic agents not only causes acute bone marrow (BM) suppression but also leads to long-term residual hematopoietic injury. This later effect has been attributed to the damage to hematopoietic stem cell (HSC) self-renewal. Using a mouse model, we investigated whether IR induces senescence in HSCs, as induction of HSC senescence can lead to the impairment of HSC self-renewal. The results showed that exposure of C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) resulted in a long-lasting quantitative and qualitative reduction in HSCs (Lin− c-kit+ Sca-1+ or LKS+ cells). Compared to control HSCs, HSCs from irradiated BM at 4 weeks after TBI exhibited a significant reduction in day-35 CAFC frequency and deficiency in cell proliferation and colony formation in a single cell culture assay stimulated with SCF/TPO and SCF/TPO/IL-3, respectively. In addition, transplantation of irradiated HSCs (500 LKS+ cells/recipient) produced less than 1% long-term (2-month) engraftment in a competitive repopulation assay while transplantation of the same number of control HSCs resulted in 24.8% engraftment. Furthermore, HSCs from irradiated mice expressed increased levels of p16Ink4a and senescence-associated beta-galactosidase (SA-beta-gal), two commonly used biomarkers of cellular senescence. In contrast, hematopoietic progenitor cells (Lin− c-kit+ Sca-1− or LKS− cells) from irradiated mice did not show significant changes in clonogenesity in a CFU assay and expressed minimal levels of p16Ink4a and SA-beta-gal. These results suggest that exposure to IR can induce senescence selectively in HSCs but not in HPCs. Interestingly, this IR- induced HSC senescence was associated with a prolonged elevation of p21Cip1/Waf1, p16Ink4a and p19ARF mRNA expression, whereas the expression of p27Kip1, p18Ink4c and p19 Ink4d mRNA was not increased. This suggests that p21Cip1/Waf1, p16Ink4a and p19ARF may play an important role in IR-induced senescence in HSCs, since their expression has been implicated in the initiation, establishment and maintenance of cellular senescence. Therefore, these findings provide valuable insights into the mechanisms underlying IR-induced long-term BM damage. This could lead to the discovery of novel molecular targets for intervention to circumvent IR-induced BM toxicity. In addition, understanding how normal HSCs senesce after IR and chemotherapy will help us to elucidate the molecular mechanisms whereby leukemia/cancer stem cells evade these cancer treatments and provide better knowledge of organismal aging.

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Long term dose response study of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced urinary bladder carcinogenesis

Cancer Letters ◽

10.1016/0304-3835(83)90234-3 ◽

1983 ◽

Vol 18 (3) ◽

pp. 261-269 ◽

Cited By ~ 8

Author(s):

Masayuki Arai ◽

Margaret St. John ◽

Shoji Fukushima ◽

Gilbert H. Friedell ◽

Samuel M. Cohen

Keyword(s):

Urinary Bladder ◽

Dose Response ◽

Bladder Carcinogenesis ◽

Dose Response Study

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Long-term effects of acute low-dose ionizing radiation on the neonatal mouse heart: a proteomic study

Radiation and Environmental Biophysics ◽

10.1007/s00411-013-0483-8 ◽

2013 ◽

Vol 52 (4) ◽

pp. 451-461 ◽

Cited By ~ 18

Author(s):

Mayur V. Bakshi ◽

Zarko Barjaktarovic ◽

Omid Azimzadeh ◽

Stefan J. Kempf ◽

Juliane Merl ◽

...

Keyword(s):

Ionizing Radiation ◽

Low Dose ◽

Neonatal Mouse ◽

Mouse Heart ◽

Long Term Effects ◽

Proteomic Study

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Ionizing Radiation Induces Hematopoietic Stem Cell Senescence and Long-Term Bone Marrow Suppression in a p16Ink4a/Arf-Independent manner

Blood ◽

10.1182/blood.v118.21.1345.1345 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1345-1345

Author(s):

Lijian Shao ◽

Wei Feng ◽

Hongliang Li ◽

Yong Wang ◽

Norman Sharpless ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Ionizing Radiation ◽

Hematopoietic Stem Cell ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Sublethal Dose ◽

Independent Manner ◽

Hematopoietic Stem

Abstract Abstract 1345 Many patients receiving chemotherapy and/or ionizing radiation (IR) develop residual (or long-term) bone marrow (BM) injury that can not only limit the success of cancer treatment but also adversely affect their quality of life. Although residual BM injury has been largely attributed to the induction of hematopoietic stem cell (HSC) senescence, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury. The Ink4a-Arf locus encodes two important tumor suppressors, p16Ink4a (p16) and Arf. Both of them have been implicated in mediating the induction of cellular senscence in a variety of cells including HSCs. Therefore, we examined the role of p16 and/or Arf in IR-induced HSC senescence and long-term BM suppression using a total body irradiation (TBI) mouse model. The results from our studies show that exposure of wild-type (WT) mice to a sublethal dose (6 Gy) of TBI induces HSC senescence and long-term BM suppression. The induction of HSC senescence is not associated with a reduction in telemore length in HSCs and their progeny, but is associated with significant increases in the production of reactive oxygen species (ROS), the expression of p16 and Arf mRNA, and the activity of senescence-associated β-galacotosidase (SA-β-gal) in HSCs. However, genetical deletion of Ink4a and/or Arf has no effect on TBI-induced HSC senescence, as HSCs from the Ink4a and/or Arf knockout mice after exposure to TBI exhibit similar changes as those seen in the cells from irradiated WT mice in comparison with the cells from un-irradiated mice with correspondent genotypes. In addition, TBI-induced long-term BM suppression is also not attenuated by the deletion of the Ink4a and/or Arf genes. These findings suggest that IR induces HSC senescence and long-term BM suppression in a p16Ink4a/Arf-independent manner. Disclosures: No relevant conflicts of interest to declare.

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Hiatus in Infant Acute Leukemia Incidence rates in Belarus: Adaptation-to-Low-Dose-Radiation Phenomenon?

Blood ◽

10.1182/blood.v118.21.507.507 ◽

2011 ◽

Vol 118 (21) ◽

pp. 507-507

Author(s):

Vadim Ivanov ◽

Tatiana Terehovich ◽

Eugene Ivanov

Keyword(s):

Ionizing Radiation ◽

Acute Leukemia ◽

Radiation Exposure ◽

Low Dose ◽

Incidence Rates ◽

Low Dose Radiation ◽

Infant Leukemia ◽

Dose Radiation ◽

Group 1

Abstract Abstract 507 The question of whether child acute leukemia (ChAL) incidence has changed as a result of Chernobyl is of great scientific and public interest. Our initial report (Nature, 1993) showed no increase in the incidence rates (IR) of ChAL in Belarus in the whole group of children (0–14 y.o.) 5 years (1986 – 1991) after accident. This data were confirmed in several European countries. As concerns infant's AL (0–1 y.o.), Petridou et al. reported 2.6 times increase of AL in Greek infants, exposed in utero to Chernobyl radiation. No significant difference in IR was found among children aged 1 – 4 y.o. or older. All epidemiological data concerning separate analysis of infant (0–1 y.o.) ChL was concentrated on the first decade after Chernobyl and no any systematic data is available after 1996. Since 1979 the occurrence of leukemia has been documented accurately through the Registry of Blood diseases. The patients had to be inhabitants of Belarus and were grouped by age at diagnosis. AL diagnostic accuracy was confirmed by the international experts. Rates were standardized directly to the standard world population. We present the age-cohort-period analyses of IR trends of ChAL from 1979 to 2006 in Belarus. It comprised 1077 ChAL cases (0–4 y.o.). Number of cases and equivalent doses of whole body radiation exposure was tabulated by age at diagnosis and period of observation (seven pre-accident years, 1979–1985) and post-accident 7-year periods: 1986–1992, 1993–1999 and 2000–2006. During first 7 years after the accident (1986–1992) the IR of infant AL (0–1 y.o.) increased significantly – from 49 (IR=4.33) before Chernobyl to 67 cases (IR=6.36) in 1986–1992 (RR=1.47; p=0.04). Older age group (1–4 y.o.) did not show any increase in ChAL rates. Following 7-years period (1993–1999) revealed the statistically significant decrease of incidence of infant leukemia: from 49 (IR=4.33) before Chernobyl to 16 cases (IR=2.29) in 1993–1999 years (RR=0.53; p=0.024). Surprisingly, during the next 7 years (2000–2006) we found a further decrease of the incidence of infant leukemia with only 3 cases (IR=0.47) in 7 years. It is highly significant when compared with 49 cases (IR=4.33) before Chernobyl (p= 0.0000053, RR=0.11) and 67 cases (IR=6.36) appeared during first 7 years following Chernobyl accident (p < 0.0000001, RR=0.04). As concerns the older group (1–4 y.o.) we did not find any decrease of IR into the second (1993–1999) and third (2000–2006) 7-year periods. Actually we are working on the next time period (2007–2010) and new upgraded data will be presented. Long-term analysis of incidence of post-Chernobyl childhood acute leukemia permitted to discover the biphasic dynamics of infant's AL incidence rate. Significant increase into the first 7-year period followed by dramatic decrease between year +8 and year + 21. From radiological point of view it is relatively simpler to explain the increase into the first 7 years, because ionizing radiation is one of the few exposures for which the casual relationship with childhood leukemia has been established. Much more difficult to explain following after decrease in incidence rate of infant leukemia in Belarus. Can we speculate about the “adaptation-to-radiation” mechanisms? Over the past decades the growing body of data from cell cultures, experimental animals and humans suggests that low-dose ionizing radiation may have some beneficial (hormetic or adoptive) effect. Several epidemiological studies (India, China, Japan, USA) of a long-term low dose environmental irradiation are in favor of the hypothesis of radiation hormesis or adaptation. The carcinogenic effects of low dose radiation exposure may be restricted to children exposed in utero or in early infancy (0-12 months) during the first years after explosion. Following after dramatic decrease of IRs of infant leukemia might be explained by the developing of adaptive response to chronic low dose ionizing radiation exposure. The presented data may be one of the first clinical evidence concerning human ability of adaptation to long-term low dose radiation. Disclosures: No relevant conflicts of interest to declare.

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