Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53

Li,Si-Jie; Liang,Xin-Yue; Li,Hai-Jun; Li,Wei; Zhou,Lei; Chen,Hua-Qiu; Ye,Song-Gen; Yu,De-Hai; Cui,Jiu-Wei

doi:10.3892/ijo.2016.3795

Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53

Authors:
- Si-Jie Li
- Xin-Yue Liang
- Hai-Jun Li
- Wei Li
- Lei Zhou
- Hua-Qiu Chen
- Song-Gen Ye
- De-Hai Yu
- Jiu-Wei Cui
View Affiliations

Affiliations: Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Clinical Medicine, Norman Bethane Health Science Center, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: December 6, 2016 https://doi.org/10.3892/ijo.2016.3795
Pages: 290-296

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells. Through cell cycle analyses, we found that LDIR accelerated cell cycle into S phase in MDA-MB-231 cells, but did not affect the cell cycle of Hs 578Bst cells. Using western blotting, we demonstrated that the expression of CDK4, CDK6 and cyclin D1 was upregulated in MDA-MB-231 cells after LDIR. Although LDIR increased ataxia-telangiectasia mutated (ATM) level in both MDA-MB-231 cells and Hs 578Bst cells and activated ATM/p53/p21 pathway, only the mutant type of p53 (mtp53) protein in MDA-MB-231 cells was shown to be accumulated after LDIR. Using ATM inhibitor or lentivirus-mediated small interfering RNA (siRNA) to block the ATM/p53/p21 pathway in MDA-MB-231 cells, the LDIR-induced cell proliferation was abolished. When we introduced wild-type p53 (wtp53) protein into MDA-MB-231 cells, the LDIR-induced cell proliferation was also abolished. These findings suggest that normal p53 function is crucial in ATM/p53/p21 pathway activated by LDIR. The p53 status is the most probable reason leading to differential LDIR biological activities between breast tumor cells and normal breast cells.

View Figures

View References

1	GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Default.aspx. Access date: June 10, 2016.
2	Rodin D, Knaul FM, Lui TY and Gospodarowicz M: Radiotherapy for breast cancer: The predictable consequences of an unmet need. Breast. 29:120–122. 2016. View Article : Google Scholar : PubMed/NCBI
3	Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH and Wolmark N: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 347:1233–1241. 2002. View Article : Google Scholar : PubMed/NCBI
4	Kim JJ and Tannock IF: Repopulation of cancer cells during therapy: An important cause of treatment failure. Nat Rev Cancer. 5:516–525. 2005. View Article : Google Scholar : PubMed/NCBI
5	Peitzsch C, Kurth I, Kunz-Schughart L, Baumann M and Dubrovska A: Discovery of the cancer stem cell related determinants of radioresistance. Radiother Oncol. 108:378–387. 2013. View Article : Google Scholar : PubMed/NCBI
6	Luckey TD: physiological benefits from low levels of ionizing radiation. Health Phys. 43:771–789. 1982. View Article : Google Scholar : PubMed/NCBI
7	Feinendegen LE: Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol. 78:3–7. 2005. View Article : Google Scholar : PubMed/NCBI
8	Olivieri G, Bodycote J and Wolff S: Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science. 223:594–597. 1984. View Article : Google Scholar : PubMed/NCBI
9	Li W, Wang G, Cui J, Xue L and Cai L: Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation. Exp Hematol. 32:1088–1096. 2004. View Article : Google Scholar : PubMed/NCBI
10	Liang X, So YH, Cui J, Ma K, Xu X, Zhao Y, Cai L and Li W: The low-dose ionizing radiation stimulates cell proliferation via activation of the MAPK/ERK pathway in rat cultured mesenchymal stem cells. J Radiat Res (Tokyo). 52:380–386. 2011. View Article : Google Scholar
11	Jiang H, Xu Y, Li W, Ma K, Cai L and Wang G: Low-dose radiation does not induce proliferation in tumor cells in vitro and in vivo. Radiat Res. 170:477–487. 2008. View Article : Google Scholar : PubMed/NCBI
12	Lee CL, Blum JM and Kirsch DG: Role of p53 in regulating tissue response to radiation by mechanisms independent of apoptosis. Transl Cancer Res. 2:412–421. 2013.
13	Menon V and Povirk L: Involvement of p53 in the repair of DNA double strand breaks: Multifaceted roles of p53 in homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Subcell Biochem. 85:321–336. 2014. View Article : Google Scholar : PubMed/NCBI
14	Freed-Pastor WA and Prives C: Mutant p53: One name, many proteins. Genes Dev. 26:1268–1286. 2012. View Article : Google Scholar : PubMed/NCBI
15	Kim JS, Lee C, Bonifant CL, Ressom H and Waldman T: Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Mol Cell Biol. 27:662–677. 2007. View Article : Google Scholar :
16	Zhang H, Zeitz MJ, Wang H, Niu B, Ge S, Li W, Cui J, Wang G, Qian G, Higgins MJ, et al: Long noncoding RNA-mediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 204:61–75. 2014. View Article : Google Scholar : PubMed/NCBI
17	Lindell B and Sowby D: The 1958 UNSCEAR report. J Radiol Prot. 28:277–282. 2008. View Article : Google Scholar : PubMed/NCBI
18	Kadhim M, Salomaa S, Wright E, Hildebrandt G, Belyakov OV, Prise KM and Little MP: Non-targeted effects of ionising radiation - implications for low dose risk. Mutat Res. 752:84–98. 2013. View Article : Google Scholar
19	Stankevicins L, Almeida da Silva AP, Ventura Dos Passos F, Dos Santos Ferreira E, Menks Ribeiro MC, G David M, J Pires E, Ferreira-Machado SC, Vassetzky Y, de Almeida CE, et al: MiR-34a is up-regulated in response to low dose, low energy X-ray induced DNA damage in breast cells. Radiat Oncol. 8:2312013. View Article : Google Scholar : PubMed/NCBI
20	Lehrer S and Rosenzweig KE: Lung cancer hormesis in high impact states where nuclear testing occurred. Clin Lung Cancer. 16:152–155. 2015. View Article : Google Scholar
21	Dobrzynski L, Fornalski KW and Feinendegen LE: Cancer mortality among people living in areas with various levels of natural background radiation. Dose Response. 13:15593258155923912015. View Article : Google Scholar : PubMed/NCBI
22	Mettler FA, Sinclair WK, Anspaugh L, Edington C, Harley JH, Ricks RC, Selby PB, Webster EW and Wyckoff HO: The 1986 and 1988 UNSCEAR (United nations Scientific Committee on the Effects of Atomic Radiation) reports: Findings and implications. Health Phys. 58:241–250. 1990. View Article : Google Scholar : PubMed/NCBI
23	Yang G, Li W, Jiang H, Liang X, Zhao Y, Yu D, Zhou L, Wang G, Tian H, Han F, et al: Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics. Int J Cancer. 139:2157–2168. 2016. View Article : Google Scholar : PubMed/NCBI
24	Liu SZ: On radiation hormesis expressed in the immune system. Crit Rev Toxicol. 33:431–441. 2003. View Article : Google Scholar : PubMed/NCBI
25	Bartek J, Iggo R, Gannon J and Lane DP: Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene. 5:893–899. 1990.PubMed/NCBI
26	Cadwell C and Zambetti GP: The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth. Gene. 277:15–30. 2001. View Article : Google Scholar : PubMed/NCBI
27	Shaulsky G, Goldfinger N and Rotter V: Alterations in tumor development in vivo mediated by expression of wild type or mutant p53 proteins. Cancer Res. 51:5232–5237. 1991.PubMed/NCBI
28	Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C and Levine AJ: Gain of function mutations in p53. Nat Genet. 4:42–46. 1993. View Article : Google Scholar : PubMed/NCBI
29	Yan W, Zhang Y, Zhang J, Liu S, Cho SJ and Chen X: Mutant p53 protein is targeted by arsenic for degradation and plays a role in arsenic-mediated growth suppression. J Biol Chem. 286:17478–17486. 2011. View Article : Google Scholar : PubMed/NCBI