Sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKbeta.
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-kappaB activation. Here, we demonstrate that sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKbeta activity. More specifically, when we compared two different human breast cancer cell lines, Hs578T, which has relatively low basal IKKbeta activity, and MDA-MB231, which has relatively high basal IKKbeta 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 IKKbeta, 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 IKKbeta and the subsequent p38 MAPK-dependent activation of JNK1.
Seo
A-Mi
AM
Research Center for Women's Diseases, Division of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Korea.
Hong
Seung-Woo
SW
Shin
Jae-Sik
JS
Park
In-Chul
IC
Hong
Nam-Joo
NJ
Kim
Dae-Jin
DJ
Lee
Won-Keun
WK
Lee
Wang-Jae
WJ
Jin
Dong-Hoon
DH
Lee
Myeong-Sok
MS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D034741:RNA, Small Interfering; D013467:Sulindac; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases