Oct4 suppresses IR‑induced premature senescence in breast cancer cells through STAT3- and NF‑κB-mediated IL‑24 production

Kim,Jeong-Yub; Kim,Jeong-Chul; Lee,Ji-Yun; Park,Myung-Jin

doi:10.3892/ijo.2018.4391

Oct4 suppresses IR‑induced premature senescence in breast cancer cells through STAT3- and NF‑κB-mediated IL‑24 production

Authors:
- Jeong-Yub Kim
- Jeong-Chul Kim
- Ji-Yun Lee
- Myung-Jin Park
View Affiliations

Affiliations: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea, Department of Pathology, College of Medicine, Korea University, Seoul 02841, Republic of Korea
Published online on: May 2, 2018 https://doi.org/10.3892/ijo.2018.4391
Pages: 47-58
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells that have been proposed to be a primary cause of failure of therapies, including ionizing radiation (IR). Their embryonic stem-like signature is associated with poor clinical outcome. In the present study, the function of octamer-binding transcription factor 4 (Oct4), an embryonic stem cell factor, in the resistance of BCSCs to IR was investigated. Mammosphere cells exhibited increased expression of stemness-associated genes, including Oct4 and sex‑determining region Y‑box 2 (Sox2), and were more resistant to IR compared with serum-cultured monolayer cells. IR‑resistant MCF7 cells also exhibited significantly increased expression of Oct4. To investigate the possible involvement of Oct4 in IR resistance of breast cancer cells, cells were transfected with Oct4. Ectopic expression of Oct4 increased the clonogenic survival of MCF7 cells following IR, which was reversed by treatment with small interfering RNA (siRNA) targeting Oct4. Oct4 expression decreased phosphorylated histone H2AX (γ-H2AX) focus formation and suppressed IR‑induced premature senescence in these cells. Mammosphere, IR‑resistant and Oct4‑overexpressing MCF7 cells exhibited enhanced phosphorylation of signal transducer and activation of transcription 3 (STAT3) (Tyr705) and inhibitor of nuclear factor κB (NF‑κB), and blockade of these pathways with siRNA against STAT3 and/or specific inhibitors of STAT3 and NF‑κB significantly increased IR‑induced senescence. Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL‑24) expression through STAT3 and NF‑κB signaling, and siRNA against IL‑24 increased IR‑induced senescence, whereas recombinant human IL‑24 suppressed it. The results of the present study indicated that Oct4 confers IR resistance on breast cancer cells by suppressing IR‑induced premature senescence through STAT3- and NF‑κB-mediated IL‑24 production.

View Figures

View References

1	Parkin DM, Pisani P and Ferlay J: Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 80:827–841. 1999. View Article : Google Scholar : PubMed/NCBI
2	Pantel K and Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer. 4:448–456. 2004. View Article : Google Scholar : PubMed/NCBI
3	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
4	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
5	Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003. View Article : Google Scholar : PubMed/NCBI
6	Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
7	Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA and Daidone MG: Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65:5506–5511. 2005. View Article : Google Scholar : PubMed/NCBI
8	Phillips TM, McBride WH and Pajonk F: The response of CD24(−/low)/CD44⁺ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 98:1777–1785. 2006. View Article : Google Scholar : PubMed/NCBI
9	Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AND, Qian D, Lam JS, Ailles LE, Wong M, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI
10	Karimi-Busheri F, Rasouli-Nia A, Mackey JR and Weinfeld M: Senescence evasion by MCF-7 human breast tumor-initiating cells. Breast Cancer Res. 12:R312010. View Article : Google Scholar : PubMed/NCBI
11	Takahashi K and Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 126:663–676. 2006. View Article : Google Scholar : PubMed/NCBI
12	Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, Hung SC, Chang YL, Tsai ML, Lee YY, et al: Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One. 3:e26372008. View Article : Google Scholar : PubMed/NCBI
13	Wang XQ, Ongkeko WM, Chen L, Yang ZF, Lu P, Chen KK, Lopez JP, Poon RTP and Fan ST: Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology. 52:528–539. 2010. View Article : Google Scholar : PubMed/NCBI
14	Du Z, Jia D, Liu S, Wang F, Li G, Zhang Y, Cao X, Ling EA and Hao A: Oct4 is expressed in human gliomas and promotes colony formation in glioma cells. Glia. 57:724–733. 2009. View Article : Google Scholar
15	Hu T, Liu S, Breiter DR, Wang F, Tang Y and Sun S: Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 68:6533–6540. 2008. View Article : Google Scholar : PubMed/NCBI
16	Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A and Weinberg RA: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 40:499–507. 2008. View Article : Google Scholar : PubMed/NCBI
17	Debacq-Chainiaux F, Erusalimsky JD, Campisi J and Toussaint O: Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 4:1798–1806. 2009. View Article : Google Scholar : PubMed/NCBI
18	Duru N, Fan M, Candas D, Menaa C, Liu HC, Nantajit D, Wen Y, Xiao K, Eldridge A, Chromy BA, et al: HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin Cancer Res. 18:6634–6647. 2012. View Article : Google Scholar : PubMed/NCBI
19	Kim JS, Kim HA, Seong MK, Seol H, Oh JS, Kim EK, Chang JW, Hwang SG and Noh WC: STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers. Oncotarget. 7:7055–7065. 2016.PubMed/NCBI
20	Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E III and Zhang Y: Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA. 104:16158–16163. 2007. View Article : Google Scholar : PubMed/NCBI
21	Ahmed KM, Zhang H and Park CC: NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells. Cancer Res. 73:3737–3748. 2013. View Article : Google Scholar : PubMed/NCBI
22	Veuger SJ, Hunter JE and Durkacz BW: Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. Oncogene. 28:832–842. 2009. View Article : Google Scholar
23	Kunigal S, Lakka SS, Joseph P, Estes N and Rao JS: Matrix metalloproteinase-9 inhibition down-regulates radiation-induced nuclear factor-kappa B activity leading to apoptosis in breast tumors. Clin Cancer Res. 14:3617–3626. 2008. View Article : Google Scholar : PubMed/NCBI
24	Jiang H, Su ZZ, Lin JJ, Goldstein NI, Young CS and Fisher PB: The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci USA. 93:9160–9165. 1996. View Article : Google Scholar : PubMed/NCBI
25	Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC, Goldstein NI and Fisher PB: The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA. 95:14400–14405. 1998. View Article : Google Scholar : PubMed/NCBI
26	Saeki T, Mhashilkar A, Swanson X, Zou-Yang XH, Sieger K, Kawabe S, Branch CD, Zumstein L, Meyn RE, Roth JA, et al: Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene. 21:4558–4566. 2002. View Article : Google Scholar : PubMed/NCBI
27	Lebedeva IV, Su ZZ, Sarkar D, Kitada S, Dent P, Waxman S, Reed JC and Fisher PB: Melanoma differentiation associated gene-7, mda-7/interleukin-24, induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and inducing reactive oxygen species. Cancer Res. 63:8138–8144. 2003.PubMed/NCBI
28	Yacoub A, Hamed HA, Allegood J, Mitchell C, Spiegel S, Lesniak MS, Ogretmen B, Dash R, Sarkar D, Broaddus WC, et al: PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells. Cancer Res. 70:1120–1129. 2010. View Article : Google Scholar : PubMed/NCBI
29	Park MA, Yacoub A, Sarkar D, Emdad L, Rahmani M, Spiegel S, Koumenis C, Graf M, Curiel DT, Grant S, et al: PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells. Autophagy. 4:513–515. 2008. View Article : Google Scholar : PubMed/NCBI
30	Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, et al: Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res. 63:5105–5113. 2003.PubMed/NCBI
31	Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM and Chada S: Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther. 9:510–518. 2004. View Article : Google Scholar : PubMed/NCBI
32	Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC and Fisher PB: Ionizing radiation enhances therapeutic activity of mda-7/IL-24: Overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the anti-apoptotic proteins bcl-xL or bcl-2. Oncogene. 25:2339–2348. 2006. View Article : Google Scholar
33	Yacoub A, Mitchell C, Lebedeva IV, Sarkar D, Su ZZ, McKinstry R, Gopalkrishnan RV, Grant S, Fisher PB and Dent P: mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling. Cancer Biol Ther. 2:347–353. 2003. View Article : Google Scholar : PubMed/NCBI