Induction of apoptosis by Bigelovii A through inhibition of NF‑κB activity

Guan,Fuqin; Shan,Yu; Wang,Qizhi; Wang,Ming; Chen,Yu; Yin,Min; Liu,Fei; Zhao,Youyi; Zhang,Jianhua; Feng,Xu

doi:10.3892/mmr.2018.9104

Induction of apoptosis by Bigelovii A through inhibition of NF‑κB activity

Authors:
- Fuqin Guan
- Yu Shan
- Qizhi Wang
- Ming Wang
- Yu Chen
- Min Yin
- Fei Liu
- Youyi Zhao
- Jianhua Zhang
- Xu Feng
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Affiliations: College of Life Science, Nanjing Agricultural University, Nanjing, Jiangsu 210095, P.R. China, The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Jiangsu Key Laboratory for The Research and Uti1ization of Plant Resources, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, Jiangsu 210014, P.R. China
Published online on: May 30, 2018 https://doi.org/10.3892/mmr.2018.9104
Pages: 1600-1608
Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bigelovii A is a 30‑nortriterpenoid glycoside, isolated from Salicornia bigelovii Torr. Until now, the effect of Bigelovii A on breast cancer treatment was unknown. The present research indicated that Bigelovii A significantly inhibited the proliferation of human breast cancer cells (MCF‑7, MDA‑MB‑231 and MDA‑MB‑468) in a concentration‑dependent manner. It was particularly effective in MCF7 cells, with an IC50 value of 4.10±1.19 µM. The anti‑proliferative effect of Bigelovii A was ascribed to the induction of apoptosis, which was characterized by chromatin condensation, externalization of phosphatidylserine on the plasma membrane, hypodiploid DNA, activation of caspases and poly (ADP‑ribose) polymerase cleavage. Furthermore, Bigelovii A reduced B-cell lymphoma 2 (Bcl‑2) and B‑cell lymphoma‑extra large (Bcl‑xl) expression and caused disruption of mitochondrial membrane potential, which are indicative features of mitochondria‑dependent apoptotic signals. It was also identified that Bigelovii A downregulated the constitutive activation of nuclear factor (NF)‑κB, as indicated by the electrophoretic mobility gel shift assay and immunocytochemistry. Furthermore, Bigelovii A suppressed constitutive IκBα phosphorylation via inhibition of IκB kinase activity. In addition to the effects on Bcl‑2 and Bcl‑xl, Bigelovii A also downregulated the expression of the NF‑κB‑regulated gene products, Cyclin D1 and cyclooxygenase‑2. This led to the induction of apoptosis and arrest of cells at the G1 phase of the cell cycle.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Santa-Maria CA and Gradishar WJ: Changing treatment paradigms in metastatic breast cancer: Lessons learned. JAMA Oncol. 1:528–534. 2015. View Article : Google Scholar : PubMed/NCBI
3	O'Shaughnessy J: Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 10:20–29. 2005. View Article : Google Scholar : PubMed/NCBI
4	Ruland J: Return to homeostasis: Downregulation of NF-κB responses. Nat Immunol. 12:709–714. 2011. View Article : Google Scholar : PubMed/NCBI
5	Chaturvedi MM, Sung B, Yadav VR, Kannappan R and Aggarwal BB: NF-κB addiction and its role in cancer: ‘One size does not fit all’. Oncogene. 30:1615–1630. 2011. View Article : Google Scholar : PubMed/NCBI
6	Fornier MN, Rathkopf D, Shah M, Patil S, O'Reilly E, Tse AN, Hudis C, Lefkowitz R, Kelsen DP and Schwartz GK: Phase I dose finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors. Clin Cancer Res. 13:5841–5846. 2007. View Article : Google Scholar : PubMed/NCBI
7	Guan FQ, Shan Y, Zhao YY, Wang QZ, Wang M, Sun H, Chen Y, Yin M and Feng X: Research development on pharmacological activities and mechanism of Salicornia plants. Chin Pharm Bull. 29:1188–1191. 2013.
8	Wang QZ, Liu XF, Shan Y, Guan FQ, Chen Y, Wang XY, Wang M and Feng X: Two new nortriterpenoid saponins from Salicornia bigelovii Torr. and their cytotoxic activity. Fitoterapia. 83:742–749. 2012. View Article : Google Scholar : PubMed/NCBI
9	Yan C, Guan F, Shen Y, Tang H, Yuan D, Gao H and Feng X: Bigelovii a protects against lipopolysaccharide-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein δ pathways. Mediators Inflamm. 2016:92016042016. View Article : Google Scholar : PubMed/NCBI
10	Guan FQ, Wang HT, Shan Y, Zhang DM, Zhao YY, Chen Y, Wang QZ, Wang M and Feng X: Bigelovii A induces apoptosis of HL60 human acute promyelocytic leukaemia cells. Mol Med Rep. 7:1585–1590. 2013. View Article : Google Scholar : PubMed/NCBI
11	Guan F, Wang Q, Wang M, Shan Y, Chen Y, Yin M, Zhao Y, Feng X, Liu F and Zhang J: Isolation, identification and cytotoxicity of a new noroleanane-type triterpene saponin from Salicornia bigelovii Torr. Molecules. 20:6419–6431. 2015. View Article : Google Scholar : PubMed/NCBI
12	Wang F, Cai HY, Zhao Q, Xing T, Li JH and Wang NS: Epinephrine evokes renalase secretion via α-adrenoceptor/NF-κB pathways in renal proximal tubular epithelial cells. Kidney Blood Press Res. 39:252–259. 2014. View Article : Google Scholar : PubMed/NCBI
13	Wang F, Zhang G, Lu Z, Geurts A M, Usa K, Jacob HJ, Cowley AW, Wang N and Liang M: Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury. Kidney Int. 88:796–803. 2015. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Rabi T and Banerjee S: Novel Synthetic triterpenoid methyl 25-hydroxy-3-oxoolean-12-en-28-oate induces apoptosis through JNK and p38 MAPK pathways in human breast adenocarcinoma MCF-7 cells. Mol Carcinog. 47:415–423. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yip KW and Reed JC: Bcl-2 family proteins and cancer. Oncogene. 27:6398–6406. 2008. View Article : Google Scholar : PubMed/NCBI
17	Sevilla L, Zaldumbide A, Pognonec P and Boulukos KE: Transcriptional regulation of the bcl-x gene encoding the antiapoptotic Bcl-xL protein by Ets, Rel/NF-κB, STAT and AP1 transcription factor families. Histol Histopathol. 16:595–601. 2001.PubMed/NCBI
18	Zandi E and Karin M: Bridging the gap: Composition, regulation and physiological function of the IκB kinase complex. Mol Cell Biol. 19:4547–4551. 1999. View Article : Google Scholar : PubMed/NCBI
19	Pahl HL: Activators and target genes of Rel/NF-κB transcription factors. Oncogene. 18:6853–6866. 1999. View Article : Google Scholar : PubMed/NCBI
20	Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S and Howells L: Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene. 18:6013–6020. 1999. View Article : Google Scholar : PubMed/NCBI
21	DeSantis C, Siegel R, Bandi P and Jemal A: Breast cancer statistics. CA Cancer J Clin. 61:409–418. 2011. View Article : Google Scholar : PubMed/NCBI
22	Bishayee A, Ahmed S, Brankov N and Perloff M: Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci (Landmark Ed). 16:980–996. 2011. View Article : Google Scholar : PubMed/NCBI
23	Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK: Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ashe PC and Berry MD: Apoptotic signaling cascades. Prog Neuropsychopharmacol Biol Psychiatry. 27:199–214. 2003. View Article : Google Scholar : PubMed/NCBI
25	Gambi N, Tramontano F and Quesada P: Poly (ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines. Biochem Pharmacol. 75:2356–2363. 2008. View Article : Google Scholar : PubMed/NCBI
26	Scovassi AI and Poirier GG: Poly (ADP-ribosylation) and apoptosis. Mol Cell Biochem. 199:125–137. 1999. View Article : Google Scholar : PubMed/NCBI
27	Goldberg JE and Schwertfeger KL: Proinflammatory cytokines in breast cancer: Mechanisms of action and potential targets for therapeutics. Curr Drug Targets. 11:1133–1146. 2010. View Article : Google Scholar : PubMed/NCBI
28	Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, Lin L, Yao H, Su F, Li D, et al: A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 27:370–381. 2015. View Article : Google Scholar : PubMed/NCBI
29	Wang J, Zhao B, Yi Y, Zhang W, Wu X, Zhang L and Shen Y: Mycoepoxydiene, a fungal polyketide inhibits MCF-7 cells through simultaneously targeting p53 and NF-κB pathways. Biochem Pharmacol. 84:891–899. 2012. View Article : Google Scholar : PubMed/NCBI
30	Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G and Bishayee A: Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence. Cancer Lett. 346:206–216. 2014. View Article : Google Scholar : PubMed/NCBI
31	Baldwin AS: Regulation of cell death and autophagy by IKK and NF-κB: Critical mechanisms in immune function and cancer. Immunol Rev. 246:327–345. 2012. View Article : Google Scholar : PubMed/NCBI