Non-steroidal anti-inflammatory drugs (
NSAIDs) have been widely reported to display strong efficacy for
cancer chemoprevention, although their mechanism of action is poorly understood. The most well-documented effects of
NSAIDs include inhibition of
tumor cell proliferation and induction of apoptosis, but their effect on
tumor cell invasion has not been well studied. Here, we show that the
NSAID,
sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon
tumor cells in vitro at concentrations less than those required to inhibit
tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of
microRNA (
miRNA). A total of 132
miRNAs were found to be altered in response to SS treatment, including miR-10b, miR-17, miR-21 and miR-9, which have been previously implicated in
tumor invasion and
metastasis. We confirmed that these
miRNA can stimulate
tumor cell invasion and show that SS can attenuate their invasive effects by downregulating their expression. Employing
luciferase and
chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four
miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB. Analysis of the promoter sequences of the
miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB-binding sites. These results show that SS can inhibit
tumor cell invasion by suppressing NF-κB-mediated transcription of
miRNAs.