Abstract
BackgroundSpecificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors.MethodsThe functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs.ResultsSulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide > > sulindac sulfone > sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins.ConclusionsThe results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products.
Highlights
Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers
Sulindac sulfide induced similar responses after treatment for 48 h; at this time point, there was a pronounced downregulation of Sp1, Sp3 and Sp4 proteins in SW480 (Fig. 2c) and RKO (Fig. 2d) cells
Sulindac sulfide was the most active sulindac derivative as observed in previous studies [33, 34] and the results suggest that the growth inhibitory effects of sulindac sulfide are correlated with downregulation of pro-oncogenic Sp proteins, and previous studies show that knockdown of one or more [35, 36] Sp proteins in colon cancer cells decreases cell cycle progression and induces apoptosis
Summary
Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors. Several studies show that the use of aspirin and other NSAIDs is associated with decreased. Sulindac induced apoptosis in HT-29 colon cancer cells and this is related to downregulation of survivin which in turn is due to decreased expression of β-catenin which regulates survivin expression through the transcription factor TCF-4 [13]. Other studies show downregulation of β-catenin and/or survivin in cancer cells and tumors treated with sulindac or its metabolites [15,16,17] and the pro-apoptotic effect of survivin downregulation in head and neck sarcoma and carcinoma cells is STAT2-dependent [11, 12]
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