Abstract
Abstract Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the exact pathway has not been identified. We hypothesized that aspirin's anti-cancer effect may occur through modulation of c-Myc gene expression. Being a transcription factor, c-Myc controls nearly 15% of the expression of all genes and its activity is highly regulated in normal cells. In many cancers including colon cancer, c-Myc is mutated and constitutively activated which leads to uncontrolled cell proliferation. In the present study, we demonstrate that aspirin and its primary metabolite, salicylic acid, significantly decrease the c-Myc protein levels in colon cancer cells. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration dependent (250 μM to 2500 μM) fashion (up to 70%). Interestingly, greater inhibition was observed in the nucleus than the cytoplasm, and immuno-fluorescence studies further confirmed these observations. Pre-treatment of cells with lactacystin partially reversed the inhibitory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Transfection of HCT-116 cells with DDK-tagged c-Myc produced abundant c-Myc protein; but, it was unaffected by aspirin and salicylic acid. In the same lysates, the endogenous c-Myc level were significantly decreased. HPLC analysis showed that aspirin taken up by cells was metabolized to salicylic acid in a time-dependent fashion. This further supports the finding aspirin's inhibitory effect on c-Myc occurs through formation of salicylic acid. Our result suggests that aspirin and salicylic acid regulate c-Myc level at both transcriptional and post-transcription level. Inhibition of c-Myc levels may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues. Citation Format: Guoqiang Ai, Rakesh Dachineni, Pratik Muley, Hemachand Tummala, Jayarama B. Gunaje. Regulation of c-Myc expression by aspirin and salicylic acid in colon cancer cells through a novel pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2093. doi:10.1158/1538-7445.AM2015-2093
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