Colon cancer concept illustration. IMAGE/LMU
By PATRICK MAYOYO
Researchers at Ludwig Maximilians Universität München (LMU) have discovered a signaling pathway through which aspirin can inhibit colorectal cancer.
The scientists in their findings published in the journal Cell Death and Disease, said aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC) adding that aspirin suppresses the progression of established CRCs. However, they noted underlying molecular mechanisms are not completely understood.
“Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs,” they said in a press release.
How salicylate suppresses c-MYC
They added in addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK and the suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells.
“In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53,” the researchers noted.
Colorectal cancer, also known as bowel cancer, ranks as the world’s third most prevalent cancer type, with approximately 1.9 million new cases and 900,000 fatalities annually. Consequently, there is a critical demand for preventive measures. Aspirin/acetylsalicylic acid has proven to be one of the most promising candidates for the prevention of colorectal cancer.
Among other findings, studies have shown that when patients with cardiovascular diseases took low doses of aspirin over several years, it reduced their risk of colorectal cancer.
Furthermore, aspirin can inhibit the progression of colorectal cancer. Now a team led by Heiko Hermeking, Professor of Experimental and Molecular Pathology at LMU, has investigated which molecular mechanisms mediate these effects.
Molecular mechanisms explored
The researchers report that aspirin induces the production of two tumor-suppressive microRNA molecules (miRNAs) called miR-34a and miR-34b/c. To do this, aspirin binds to and activates the enzyme AMPK, which in turn alters the transcription factor NRF2 such that it migrates into the cell nucleus and activates the expression of the miR-34 genes. For this activation to succeed, aspirin additionally suppresses the oncogene product c-MYC, which otherwise inhibits NRF2.
The scientists say overall, the results show that the miR-34 genes are necessary for mediating the inhibiting effect of aspirin on colorectal cancer cells. Aspirin was thus unable to prevent migration, invasion, and metastasis in miR-34-deficient cancer cells.
They add it was already known that the miR-34 genes are induced by the transcription factor p53 and mediate its effects. “Our results show, however, that activation of the miR-34 genes by aspirin takes place independently of the p53 signaling pathway,” says Hermeking.
“This is important because the p53-encoding gene is the most commonly inactivated tumor suppressor gene in colorectal cancer. In most other kinds of cancer, moreover, p53 is inactivated by mutations or viruses in the majority of cases. Aspirin could therefore be employed therapeutically in such cases in the future.”
