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Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary research

TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells

Authors: Xiao Wu, Meng-Yao Wu, Min Jiang, Qiaoming Zhi, Xiaojie Bian, Meng-Dan Xu, Fei-Ran Gong, Juan Hou, Min Tao, Liu-Mei Shou, Weiming Duan, Kai Chen, Meng Shen, Wei Li

Published in: Cancer Cell International | Issue 1/2017

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Abstract

Purpose

Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells.

Methods

Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay.

Results

TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU.

Conclusion

TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.
Literature
1.
2.
Lian L, Li W, Li ZY, Mao YX, Zhang YT, Zhao YM, Chen K, Duan WM, Tao M. Inhibition of MCF-7 breast cancer cell-induced platelet aggregation using a combination of antiplatelet drugs. Oncol Lett. 2013;5(2):675–80.PubMed
3.
Li W, Liang RR, Zhou C, Wu MY, Lian L, Yuan GF, Wang MY, Xie X, Shou LM, Gong FR, et al. The association between expressions of Ras and CD68 in the angiogenesis of breast cancers. Cancer Cell Int. 2015;15(1):17.CrossRefPubMedPubMedCentral
4.
Shou LM, Zhang QY, Li W, Xie X, Chen K, Lian L, Li ZY, Gong FR, Dai KS, Mao YX, et al. Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of alpha2 integrin. Oncol Rep. 2013;30(3):1059–66.PubMedPubMedCentral
5.
Majeed W, Aslam B, Javed I, Khaliq T, Muhammad F, Ali A, Raza A. Breast cancer: major risk factors and recent developments in treatment. Asian Pacific J Cancer Prev: APJCP. 2014;15(8):3353–8.CrossRef
6.
Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114(2):181–90.CrossRefPubMed
7.
Zheng L, Bidere N, Staudt D, Cubre A, Orenstein J, Chan FK, Lenardo M. Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol Cell Biol. 2006;26(9):3505–13.CrossRefPubMedPubMedCentral
8.
Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem. 2003;278(51):51613–21.CrossRefPubMed
9.
Tomita A, Fuchino Y, Otsuka K, Shinohara T, Tanaka SN, Umeno T, Ikeda S. Clinical effects of exogenous/endogenous TNF therapy on metastatic lesions of 34 colorectal cancer patients. Anticancer Res. 1998;18(5D):3937–9.PubMed
10.
Watanabe N, Niitsu Y, Sone H, Neda H, Urushizaki I, Yamamoto A, Nagamuta M, Sugawara Y. Therapeutic effect of endogenous tumor necrosis factor on ascites Meth A sarcoma. J Immunopharmacol. 1986;8(2):271–83.CrossRefPubMed
11.
Bertrand F, Rochotte J, Colacios C, Montfort A, Tilkin-Mariame AF, Touriol C, Rochaix P, Lajoie-Mazenc I, Andrieu-Abadie N, Levade T, et al. Blocking tumor necrosis factor alpha enhances CD8 T-cell-dependent immunity in experimental melanoma. Cancer Res. 2015;75(13):2619–28.CrossRefPubMed
12.
Jayasooriya RG, Moon DO, Park SR, Choi YH, Asami Y, Kim MO, Jang JH, Kim BY, Ahn JS, Kim GY. Combined treatment with verrucarin A and tumor necrosis factor-alpha sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas. Environ Toxicol Pharmacol. 2013;36(2):303–10.CrossRefPubMed
13.
Moon DO, Kim MO, Lee JD, Choi YH, Kim GY. Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. Cancer Lett. 2010;288(2):183–91.CrossRefPubMed
14.
Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X. Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 2010;101(5):1226–33.CrossRefPubMed
15.
Yasui H, Adachi M, Imai K. Combination of tumor necrosis factor-alpha with sulindac augments its apoptotic potential and suppresses tumor growth of human carcinoma cells in nude mice. Cancer. 2003;97(6):1412–20.CrossRefPubMed
16.
Yasukawa M, Fujihara H, Fujimori H, Kawaguchi K, Yamada H, Nakayama R, Yamamoto N, Kishi Y, Hamada Y, Masutani M. Synergetic effects of PARP inhibitor AZD2281 and cisplatin in oral squamous cell carcinoma in vitro and in vivo. Int J Mol Sci. 2016;17(3):272.CrossRefPubMedPubMedCentral
17.
Kutty RV, Chia SL, Setyawati MI, Muthu MS, Feng SS, Leong DT. In vivo and ex vivo proofs of concept that cetuximab conjugated vitamin E TPGS micelles increases efficacy of delivered docetaxel against triple negative breast cancer. Biomaterials. 2015;63:58–69.CrossRefPubMed
18.
Li W, Chen Z, Zong Y, Gong F, Zhu Y, Lv J, Zhang J, Xie L, Sun Y, Miao Y, et al. PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKalpha and sustained activation of the NF-kappaB pathway. Cancer Lett. 2011;304(2):117–27.CrossRefPubMed
19.
Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112–23.CrossRefPubMedPubMedCentral
20.
Matsudaira H, Furuno I, Ueno AM, Shinohara K, Yoshizawa K. Induction and repair of strand breaks and 3′-hydroxy terminals in the DNA of mammalian cells in culture following gamma-ray irradiation. Biochim Biophys Acta. 1977;476(2):97–107.CrossRefPubMed
21.
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol: CB. 2000;10(15):886–95.CrossRefPubMed
22.
Podhorecka M, Skladanowski A, Bozko P. H2AX phosphorylation: its role in DNA damage response and cancer therapy. J nucleic acids. 2010;2010.
23.
Hu Q, Rijcken CJ, Bansal R, Hennink WE, Storm G, Prakash J. Complete regression of breast tumour with a single dose of docetaxel-entrapped core-cross-linked polymeric micelles. Biomaterials. 2015;53:370–8.CrossRefPubMed
24.
Plaimee P, Weerapreeyakul N, Barusrux S, Johns NP. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015;48(1):67–77.CrossRefPubMed
25.
Grem JL, Fischer PH. Enhancement of 5-fluorouracil’s anticancer activity by dipyridamole. Pharmacol Ther. 1989;40(3):349–71.CrossRefPubMed
26.
Chang YJ, Hsu SL, Liu YT, Lin YH, Lin MH, Huang SJ, Ho JA, Wu LC. Gallic acid induces necroptosis via TNF-alpha signaling pathway in activated hepatic stellate cells. PLoS ONE. 2015;10(3):e0120713.CrossRefPubMedPubMedCentral
27.
Miwa S, Yano S, Kimura H, Yamamoto M, Toneri M, Matsumoto Y, Uehara F, Hiroshima Y, Murakami T, Hayashi K, et al. Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging. Cell Cycle. 2015;14(4):621–9.CrossRefPubMed
28.
Miwa S, Yano S, Kimura H, Yamamoto M, Toneri M, Murakami T, Hayashi K, Yamamoto N, Fujiwara T, Tsuchiya H, et al. Heterogeneous cell-cycle behavior in response to UVB irradiation by a population of single cancer cells visualized by time-lapse FUCCI imaging. Cell Cycle. 2015;14(12):1932–7.CrossRefPubMedPubMedCentral
29.
Shackelford RE, Kaufmann WK, Paules RS. Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ Health Perspect. 1999;107(Suppl 1):5–24.CrossRefPubMedPubMedCentral
30.
Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, Arnold A. The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev. 1999;20(4):501–34.PubMed
31.
van de Loosdrecht AA, Ossenkoppele GJ, Beelen RH, Broekhoven MG, Langenhuijsen MM. Cell cycle specific effects of tumor necrosis factor alpha in monocyte mediated leukemic cell death and the role of beta 2-integrins. Cancer Res. 1993;53(18):4399–407.PubMed
32.
Joyce D, Bouzahzah B, Fu M, Albanese C, D’Amico M, Steer J, Klein JU, Lee RJ, Segall JE, Westwick JK, et al. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway. J Biol Chem. 1999;274(36):25245–9.CrossRefPubMed
33.
Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991;65(4):701–13.CrossRefPubMed
34.
Mumberg D, Wick M, Burger C, Haas K, Funk M, Muller R. Cyclin ET, a new splice variant of human cyclin E with a unique expression pattern during cell cycle progression and differentiation. Nucleic Acids Res. 1997;25(11):2098–105.CrossRefPubMedPubMedCentral
35.
Tracey KJ, Cerami A. Tumor necrosis factor: an updated review of its biology. Crit Care Med. 1993;21(10 Suppl):S415–22.PubMed
36.
Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3(9):745–56.CrossRefPubMed
37.
Degterev A, Zhou W, Maki JL, Yuan J. Assays for necroptosis and activity of RIP kinases. Methods Enzymol. 2014;545:1–33.CrossRefPubMed
38.
Wei B, Yue P, Qingwei L. The molecular mechanism of necroptosis. Yi chuan=Hereditas/Zhongguo yi chuan xue hui bian ji. 2014;36(6):519–24.
39.
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313–21.CrossRefPubMed
40.
Zhang DW, Zheng M, Zhao J, Li YY, Huang Z, Li Z, Han J. Multiple death pathways in TNF-treated fibroblasts: RIP3- and RIP1-dependent and independent routes. Cell Res. 2011;21(2):368–71.CrossRefPubMedPubMedCentral
41.
Lu JV, Weist BM, van Raam BJ, Marro BS, Nguyen LV, Srinivas P, Bell BD, Luhrs KA, Lane TE, Salvesen GS, et al. Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity. Proc Natl Acad Sci USA. 2011;108(37):15312–7.CrossRefPubMedPubMedCentral
42.
Xie T, Peng W, Yan C, Wu J, Gong X, Shi Y. Structural insights into RIP3-mediated necroptotic signaling. Cell reports. 2013;5(1):70–8.CrossRefPubMed
43.
Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39(3):443–53.CrossRefPubMed
Metadata
Title
TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells
Authors
Xiao Wu
Meng-Yao Wu
Min Jiang
Qiaoming Zhi
Xiaojie Bian
Meng-Dan Xu
Fei-Ran Gong
Juan Hou
Min Tao
Liu-Mei Shou
Weiming Duan
Kai Chen
Meng Shen
Wei Li
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-017-0382-1

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