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.

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

“…In this context, it is important to note that several TFs, such as c-Myc [48], CREB (cyclic AMP response element binding protein) and CREM (cyclic AMP response element modulators) [49] have been implicated in the transcription of cyclin A2 gene; and which of these TFs are affected by these two drugs requires additional study. In fact, in a recent study we reported the ability of aspirin and salicylic acid to down-regulate c-Myc protein and mRNA in cancer cells [50]. Therefore, it is likely that the decreased levels of cyclin A2 mRNA or CDK2 mRNAs observed in aspirin and salicylic acid treated cells is not a non-specific effect due to a general cell cycle arrest, but most likely due to the down-regulations of TFs.…”

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells

“…Through screening and analyzing relevant websites and database online, and with the help of previous literature [7, 12, 27, 28], we thought that there were some genes which might contribute to the phenomena of tamoxifen resistance. For example, ERα protein is the target of tamoxifen, the transcription of PGR is dependent on the ERα activating estrogen response element (ERE) and also code PR protein, while its level can reflect the function of ERα.…”

“…But the exact mechanisms of aspirin that exert its anti-tumor effect are yet to be elucidated [21, 26]. Studies have reported that aspirin and its primary metabolite salicylic acid both have the ability to decrease the mRNA and protein levels of c-myc in human colon cancer cell lines, which might be one of the mechanisms for the antineoplastic activity [27, 28]. Recently, Dachineni et al [29] have shown that aspirin and salicylic acid can down-regulate a number of cyclins and cyclin dependent kinases (CDKs) in multiple cancer cell lines, which collectively suggests that inhibitory effect may occur through down-regulation of these cell cycle regulatory proteins, providing a novel mechanism for the anti-tumor effect of aspirin and salicylic.…”

“…A few studies have reported that MYC mRNA and c-myc protein can be inhibited by salicylates such as aspirin. This in turn reveals the anti-tumor effect of salicylates on colon cancer cell lines [27, 28]. So we attempted to use this drug in ER-positive breast cancer and combined it with the SERM 4-hydroxy-tamoxifen (4-OHT).…”

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

“…Recently, its therapeutic and prophylactic effects with regard to tumor metastasis are gaining widespread interest [23–26]. Maity et al reported that aspirin could increase the expression of a set of markers, indicating a mesenchymal-to-epithelial transition (MET) in human breast carcinoma, which are most likely mediated through COX-dependent or independent pathways [27].…”