title: Aspirin and salicylic acid decrease c-Myc expression in cancer cells: a potential role in chemoprevention.
abstract: Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the pathways by which it exerts its anti-cancer effects are still not fully explored. We hypothesized that aspirin's anti-cancer effect may occur through downregulation of c-Myc gene expression. Here, we demonstrate that aspirin and its primary metabolite, salicylic acid, decrease the c-Myc protein levels in human HCT-116 colon and in few other cancer cell lines. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration-dependent fashion. Greater inhibition was observed in the nucleus than the cytoplasm, and immunofluorescence studies confirmed these observations. Pretreatment of cells with lactacystin, a proteasome inhibitor, partially prevented the downregulatory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Both drugs failed to decrease exogenously expressed DDK-tagged c-Myc protein levels; however, under the same conditions, the endogenous c-Myc protein levels were downregulated. Northern blot analysis showed that both drugs caused a decrease in c-Myc mRNA levels in a concentration-dependent fashion. High-performance liquid chromatography (HPLC) analysis showed that aspirin taken up by cells was rapidly metabolized to salicylic acid, suggesting that aspirin's inhibitory effect on c-Myc may occur through formation of salicylic acid. Our result suggests that salicylic acid regulates c-Myc level at both transcriptional and post-transcription levels. Inhibition of c-Myc may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues.
authors: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD, 57007, USA.
authors: Guoqiang
authors: G
authors: Ai
authors: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD, 57007, USA.
authors: Rakesh
authors: R
authors: Dachineni
authors: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD, 57007, USA.
authors: Pratik
authors: P
authors: Muley
authors: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD, 57007, USA.
authors: Hemachand
authors: H
authors: Tummala
authors: Department of Pharmaceutical Sciences, South Dakota State University College of Pharmacy, Avera Health and Sciences Center, Brookings, SD, 57007, USA. Jayarama.gunaje@sdstate.edu.
authors: G Jayarama
authors: GJ
authors: Bhat
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012459:Salicylates / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012459:Salicylates; D001241:Aspirin
keywords: Aspirin; Colon cancer; Proteasome; Salicylic acid; c-Myc