A large body of evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) have strong antineoplastic properties against a broad range of cancer types in early or late stage animal models of tumorigenesis. However, their use in humans for chemoprevention is limited by toxicities resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. The anticancer properties of NSAIDs are generally attributed to the suppression of tumor cell proliferation and induction of apoptosis by inhibiting cyclooxygenase (COX), although numerous studies suggest that a COX-independent mechanism may either contribute to or be fully responsible for their activity. The effect of NSAIDs on tumor cell motility and invasion has not been well studied, despite clinical studies showing that certain NSAIDs can significantly increase the survival of patients with metastatic disease. Our results show that the NSAID, sulindac sulfide (SS) can potently inhibit the motility of human breast (MDA-MB-231 and SUM1315) and colorectal (HCT116 and HT29) tumor cells by a mechanism that is distinct from its tumor cell growth and COX inhibitory activity. 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 miRNAs can stimulate tumor cell invasion and show that SS can attenuate their invasive effects (individual and cooperative) by down-regulating their expression. Employing luciferase and chromatin immunoprecipitation (ChIP) assays, NF-κB was found to bind the promoters of all four miRNAs to regulate their expression at the transcriptional level. Results from the immunofluorescence and Western Blotting assays show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB, which leads to down-regulation of these miRNAs. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB binding sites. Our results demonstrate that SS can inhibit tumor cell invasion by suppressing NF-κB mediated transcription of miRNAs, which illustrate the mechanistic basis of this novel anticancer property of sulindac on tumor progression and metastasis. We expect these results are capable of supporting future clinical trials of sulindac in patients with metastatic disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-172. doi:1538-7445.AM2012-LB-172