Bcl2-induced DNA Replication Stress Promotes Lung Carcinogenesis in Response to Space Radiation

Overview

Journal Carcinogenesis

Specialty Oncology

Date 2020 Mar 12

PMID 32157295

Citations 6

Authors

Maohua Xie

Dongkyoo Park

Gabriel L Sica

Xingming Deng

Affiliations

Soon will be listed here.

Abstract

Space radiation is characterized by high-linear energy transfer (LET) ionizing radiation. The relationships between the early biological effects of space radiation and the probability of cancer in humans are poorly understood. Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress. To test the role and mechanism of Bcl2 in high-LET space radiation-induced lung carcinogenesis, we created lung-targeting Bcl2 transgenic C57BL/6 mice using the CC10 promoter to drive Bcl2 expression selectively in lung tissues. Intriguingly, lung-targeting transgenic Bcl2 inhibits ribonucleotide reductase activity, reduces dNTP pool size and retards DNA replication fork progression in mouse bronchial epithelial cells. After exposure of mice to space radiation derived from 56iron, 28silicon or protons, the incidence of lung cancer was significantly higher in lung-targeting Bcl2 transgenic mice than in wild-type mice, indicating that Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation. The findings provide some evidence for the relative effectiveness of space radiation and Bcl-2 at inducing lung cancer in mice.

Citing Articles

MicroRNA Monitoring in Human Alveolar Macrophages from Patients with Smoking-Related Lung Diseases: A Preliminary Study.

Mirra D, Esposito R, Spaziano G, Sportiello L, Panico F, Squillante A Biomedicines. 2024; 12(5).

PMID: 38791013 PMC: 11118114. DOI: 10.3390/biomedicines12051050.

A perspective on tumor radiation resistance following high-LET radiation treatment.

Rajpurohit Y, Sharma D, Lal M, Soni I J Cancer Res Clin Oncol. 2024; 150(5):226.

PMID: 38696003 PMC: 11065934. DOI: 10.1007/s00432-024-05757-8.

Long-term space missions' effects on the human organism: what we do know and what requires further research.

Tomsia M, Ciesla J, Smieszek J, Florek S, Macionga A, Michalczyk K Front Physiol. 2024; 15:1284644.

PMID: 38415007 PMC: 10896920. DOI: 10.3389/fphys.2024.1284644.

Comprehensive analysis of novel prognosis-related proteomic signature effectively improve risk stratification and precision treatment for patients with cervical cancer.

Ji X, Chu G, Chen Y, Jiao J, Lv T, Yao Q Arch Gynecol Obstet. 2022; 307(3):903-917.

PMID: 35713693 DOI: 10.1007/s00404-022-06642-w.

Robust meta-analysis for large-scale genomic experiments based on an empirical approach.

Sikdar S BMC Med Res Methodol. 2022; 22(1):43.

PMID: 35144554 PMC: 8832678. DOI: 10.1186/s12874-022-01530-y.

References

Miller Y, Dwyer-Nield L, Keith R, Le M, Franklin W, Malkinson A . Induction of a high incidence of lung tumors in C57BL/6 mice with multiple ethyl carbamate injections. Cancer Lett. 2003; 198(2):139-44. DOI: 10.1016/s0304-3835(03)00309-4. View

Lecona E, Fernandez-Capetillo O . Replication stress and cancer: it takes two to tango. Exp Cell Res. 2014; 329(1):26-34. PMC: 4878650. DOI: 10.1016/j.yexcr.2014.09.019. View

Ray M, Wang G, Barrish J, Finegold M, Demayo F . Immunohistochemical localization of mouse Clara cell 10-KD protein using antibodies raised against the recombinant protein. J Histochem Cytochem. 1996; 44(8):919-27. DOI: 10.1177/44.8.8756763. View

Chimploy K, Diaz G, Li Q, Carter O, Dashwood W, Mathews C . E2F4 and ribonucleotide reductase mediate S-phase arrest in colon cancer cells treated with chlorophyllin. Int J Cancer. 2009; 125(9):2086-94. PMC: 2753276. DOI: 10.1002/ijc.24559. View

Klopstock N, Katzenellenbogen M, Pappo O, Sklair-Levy M, Olam D, Mizrahi L . HCV tumor promoting effect is dependent on host genetic background. PLoS One. 2009; 4(4):e5025. PMC: 2660413. DOI: 10.1371/journal.pone.0005025. View

Jackson D, Pombo A . Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J Cell Biol. 1998; 140(6):1285-95. PMC: 2132671. DOI: 10.1083/jcb.140.6.1285. View

Wang H, Wang X, Zhang P, Wang Y . The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation. DNA Repair (Amst). 2008; 7(5):725-33. DOI: 10.1016/j.dnarep.2008.01.010. View

Suman S, Datta K, Trani D, Laiakis E, Strawn S, Fornace Jr A . Relative biological effectiveness of 12C and 28Si radiation in C57BL/6J mice. Radiat Environ Biophys. 2012; 51(3):303-9. PMC: 4208103. DOI: 10.1007/s00411-012-0418-9. View

Preston D, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M . Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res. 2007; 168(1):1-64. DOI: 10.1667/RR0763.1. View

10.

Pasero P, Bensimon A, Schwob E . Single-molecule analysis reveals clustering and epigenetic regulation of replication origins at the yeast rDNA locus. Genes Dev. 2002; 16(19):2479-84. PMC: 187456. DOI: 10.1101/gad.232902. View

11.

Perl A, Tichelaar J, Whitsett J . Conditional gene expression in the respiratory epithelium of the mouse. Transgenic Res. 2002; 11(1):21-9. DOI: 10.1023/a:1013986627504. View

12.

Han B, Park D, Li R, Xie M, Owonikoko T, Zhang G . Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy. Cancer Cell. 2015; 27(6):852-63. PMC: 4470473. DOI: 10.1016/j.ccell.2015.04.010. View

13.

Xie M, Park D, You S, Li R, Owonikoko T, Wang Y . Bcl2 inhibits recruitment of Mre11 complex to DNA double-strand breaks in response to high-linear energy transfer radiation. Nucleic Acids Res. 2015; 43(2):960-72. PMC: 4333404. DOI: 10.1093/nar/gku1358. View

14.

Khanna K, Jackson S . DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27(3):247-54. DOI: 10.1038/85798. View

15.

Deng X, Ruvolo P, Carr B, May Jr W . Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci U S A. 2000; 97(4):1578-83. PMC: 26477. DOI: 10.1073/pnas.97.4.1578. View

16.

Xie M, Yen Y, Owonikoko T, Ramalingam S, Khuri F, Curran W . Bcl2 induces DNA replication stress by inhibiting ribonucleotide reductase. Cancer Res. 2013; 74(1):212-23. PMC: 3887143. DOI: 10.1158/0008-5472.CAN-13-1536-T. View

17.

Mazouzi A, Velimezi G, Loizou J . DNA replication stress: causes, resolution and disease. Exp Cell Res. 2014; 329(1):85-93. DOI: 10.1016/j.yexcr.2014.09.030. View

18.

Tchou-Wong K, Jiang Y, Yee H, LaRosa J, Lee T, Pellicer A . Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer. Am J Respir Cell Mol Biol. 2002; 27(2):186-93. DOI: 10.1165/ajrcmb.27.2.4799. View

19.

DiCosmo B, Geba G, Picarella D, Elias J, Rankin J, Stripp B . Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest. 1994; 94(5):2028-35. PMC: 294635. DOI: 10.1172/JCI117556. View

20.

Pluck A, Klasen C . Generation of chimeras by microinjection. Methods Mol Biol. 2009; 561:199-217. DOI: 10.1007/978-1-60327-019-9_13. View