Abstract
Sulindac is a non-steroidal anti-inflammatory agent with anti-tumor activities that include the induction of apoptosis in various cancer cells and the inhibition malignant transformation. However, the molecular mechanisms underlying these effects are unclear. Recently, it has been shown that sulindac can inhibit NF-κB activation. Here, we demonstrate that sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ activity. More specifically, when we compared two different human breast cancer cell lines, Hs578T, which has relatively low basal IKKβ activity, and MDA-MB231, which has relatively high basal IKKβ activity, we found that MDA-MB231 was markedly more sensitive to sulindac-induced apoptosis than Hs578T. This was associated with greater caspase-3 and -9 activity in sulindac-treated MDA-MB231 cells. Using a combination of chemical kinase inhibitors and siRNA-mediated knockdown of specific kinases, we found that sulindac inhibits IKKβ, which, in turn, leads to the p38 MAPK-dependent activation of JNK1. Together, these findings suggest that sulindac induces apoptosis in susceptible human breast cancer cells through, at least in part, the inhibition of IKKβ and the subsequent p38 MAPK-dependent activation of JNK1.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- NSAIDs:
-
Non-steroidal anti-inflammatory drugs
- IKKβ:
-
IκB kinase β
- JNK1:
-
c-Jun NH2-terminal kinase 1
- COX:
-
Cyclooxygenase
- MAPK:
-
Matogen-activated protein kinase
- NF-κB:
-
Nuclear factor kappa B
- IκB:
-
Inhibitory kappa B
References
Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH et al (1995) Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 55:3110–3116
Lim JT, Piazza GA, Han EK, Delohery TM, Li H, Finn TS et al (1999) Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell line. Biochem Pharmacol 58(7):1097–1107. doi:10.1016/S0006-2952(99)00200-2
Ikui AE, Yao Y, Zhou P, Weinstein IB (2001) Induction of apoptosis by sulindac sulfide in HL60 cells is enhanced by p21CiP1 or p27KiP1. Anticancer Res 21:2297–2303
Adachi M, Sakamoto H, Kawamura R, Wang W, Imai K, Shinomura Y (2007) Nonsteroidal anti-inflammatory drugs and oxidative stress in cancer cells. Histol Histopathol 22:437–442
Shiff SJ, Qiao L, Tsai LL, Rigas B (1995) Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 96:491–503. doi:10.1172/JCI.118060
Lee HC, Park IC, Park MJ, An S, Woo SH, Jin HO et al (2005) Sulindac and its metabolites inhibit invasion of glioblastoma cells via down-regulation of Akt/PKB and MMP-2. J Cell Biochem 94(3):597–610. doi:10.1002/jcb.20312
Reddy BS, Rao CV, Seibert K (1996) Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res 56:4566–4569
Narayanan BA, Narayanan NK, Pittman B, Reddy BS (2004) Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model. Clin Cancer Res 10:7727–7737. doi:10.1158/1078-0432.CCR-04-0732
Yamamato Y, Yin M, Ling K, Gaynor RB (1999) Sulindac inhibits activation of the NF-κB pathway. J Biol Chem 274:27307–27314. doi:10.1074/jbc.274.38.27307
Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SX (1998) IEX-1L, an apoptosis inhibitor involved in NF-κB-mediated cell survival. Science 281:998–1001. doi:10.1126/science.281.5379.998
Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest 107:241–246. doi:10.1172/JCI.11991
Kwak YT, Guo J, Shen J, Gaynor RB (2000) Analysis of domains in the IKKalpha and IKKbeta proteins that regulate their kinase activity. J Biol Chem 275:14752–14759. doi:10.1074/jbc.M001039200
Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J et al (1997) IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278(5339):860–866. doi:10.1126/science.278.5339.860
Didonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388:548–554. doi:10.1038/41493
Beg AA, Ruben SM, Scheinman RI, Haskill S, Rosen CA, Baldwin AS (1992) I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev 6:1899–1913. doi:10.1101/gad.6.10.1899
Brown K, Gerstberger S, Carlson L, Fransozo G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485–1488. doi:10.1126/science.7878466
Li Q, Lu Q, Hwang JY, Buscher D, Lee KF, Izpisua-Belmonte JC, Verma IM (1999) IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev 13:1322–1328. doi:10.1101/gad.13.10.1322
Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman R, Karin M (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189:1839–1845. doi:10.1084/jem.189.11.1839
Tanaka H, Fujita N, Tsuruo T (2005) 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. J Biol Chem 280:40965–40973. doi:10.1074/jbc.M506235200
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239–252. doi:10.1016/S0092-8674(00)00116-1
Chang L, Karin M (2001) Mammalian MAP kinas signaling cascades. Nature 410(6824):37–40. doi:10.1038/35065000
Kim TI, Jin SH, Kim WH, Kang EH, Choi KY, Kim HJ et al (2001) Prolonged activation of mitogen-activated protein kinases during NSAID-induced apoptosis in HT-29 colon cancer cells. Int J Colorectal Dis 16:167–173. doi:10.1007/s003840100301
Lim SJ, Lee YJ, Park DH, Lee E, Choi MK, Park W et al (2007) Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis. Apoptosis 12:423–431. doi:10.1007/s10495-006-0620-9
Song Z, Tong C, Liang J, Dockendorff A, Huang C, Augenlicht LH, Yang W (2007) JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo. Eur J Pharm 560:95–100. doi:10.1016/j.ejphar.2007.01.020
Dong C, Yang DD, Wysk M, Whimarsh AJ, Davis RJ, Flavell RA (1998) Defective T cell differentiation in the absence of JNK1. Science 282:2092–2095. doi:10.1126/science.282.5396.2092
Liu J, Minemoto Y, Lin A (2004) c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Mol Cell Biol 24:10844–10856. doi:10.1128/MCB.24.24.10844-10856.2004
Seo SK, Lee HC, Woo SH, Jin HO, Yoo DH, Lee SJ et al (2007) Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction. Apoptosis 12:195–209. doi:10.1007/s10495-006-0527-5
Minami T, Adachi M, Kawamura R, Zhang Y, Shinomura Y, Imai K (2005) Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity. Clin Cancer Res 11:5248–5256. doi:10.1158/1078-0432.CCR-05-0085
Tegeder I, Pfeilschifter J, Geisslinger G (2001) Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 15:2057–2072. doi:10.1096/fj.01-0390rev
Sun Y, Sinicrope FA (2005) Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. Mol Cancer Ther 4:51–59
Alpert D, Schwenger P, Han J, Vilcek J (1999) Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IkB phosphorylation and NF-kB activation. J Biol Chem 274:22176–22183. doi:10.1074/jbc.274.32.22176
Ivanov VN, Ronai Z (2000) p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kB activity and Fas expression. Oncogene 19:3003–3012. doi:10.1038/sj.onc.1203602
Monks NR, Pardee AB (2006) Targeting the NF-kB pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs. J Cell Biochem 98:221–233. doi:10.1002/jcb.20789
Oleinik NV, Krupenko NI, Krupenko SA (2007) Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene 26:7222–7230. doi:10.1038/sj.onc.1210526
Han EK, Arber N, Yamamoto H, Lim JT, Delohery T, Pamukcu R et al (1998) Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 48:195–203. doi:10.1023/A:1005924730450
Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei YK et al (2007) IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130(3):440–455. doi:10.1016/j.cell.2007.05.058
Acknowledgments
Financial support: This research was supported by the Research Center for Women’s Diseases, at the Korea Science and Engineering Foundation (KOSEF) and by a grant from Sookmyung Women’s University.
Author information
Authors and Affiliations
Corresponding authors
Additional information
A-Mi Seo and Seoug-Woo Hong have contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Seo, AM., Hong, SW., Shin, JS. et al. Sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ. Apoptosis 14, 913–922 (2009). https://doi.org/10.1007/s10495-009-0367-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-009-0367-1