Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells

Abstract

Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapyinduced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirininduced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.

Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells

“…PIK3CA mutations (or PIK3CA amplifications [ 45 ]) may result in constitutive activation of PI3K and the downstream AKT pathway, enhancing PTGS2 activity and prostaglandin E 2 synthesis and leading to inhibition of apoptosis in colorectal cancer cells [ 11 ]. Recent in vitro and in vivo studies have suggested that aspirin may suppress cancer cell growth and induce apoptosis through activation of protein kinase A ( PRKA , also referred to as AMPK), inhibition of MTOR downstream signaling, and inhibition of PI3K-induced prostaglandin E 2 synthesis [ 46 – 48 ]. The present study was designed to detect the potency of aspirin therapy in colon cancer cell lines according to major somatic driver mutations such as PIK3CA, BRAF , and KRAS mutations.…”

Aspirin and colorectal cancer chemoprevention

“…Recent studies suggest the low dose strategy works due to inactivation of platelet COX-1 -a strong induction signal for COX-2 upregulation in damaged cells [19] . Recent work also indicates there may be other isolated mechanisms [8] Cohort More than 2x per week 10 0.62 Cancer Prevention Study [9] Cohort Various 15 0.58-0.61 Health Professionals Study [10] Cohort More than 2x per week 4 0.54 of effect to prevent cancer -the phosphatidylinositol 3-kinase-related pathway [20] , "induced-senescence" by interference of the sirtuin1 metabolic pathway [21] , and clotting factor acetylation [22] .…”

Metabolic energy sensors as targets for designing host-directed therapies for tuberculosis

“…Similarly, Yang et al demonstrated that SIRT1 activators suppress the inflammatory response in an LPS‐induced inflammation mouse model by deacetylation of p65 and inhibition of NF‐κB activity. The AMPK–SIRT1 axis can also be modulated by another common drug, aspirin, to improve TB treatment outcomes . In patients with tuberculosis meningitis, aspirin resulted in a reduced frequency of stroke and reduced 3‐mo mortality .…”

“…The AMPK-SIRT1 axis can also be modulated by another common drug, aspirin, to improve TB treatment outcomes. [111][112][113] In patients with tuberculosis meningitis, aspirin resulted in a reduced frequency of stroke and reduced 3-mo mortality. 114,115 Collectively, these findings underscore the promise of AMPK/SIRT1 activators as a novel therapeutic approach for TB.…”