Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

Abstract

Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/b-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of b-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of b-catenin were assessed by immunoblotting, and also the localization of b-catenin was shown by green fluorescent protein-tagged b-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/b-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/b-catenin pathway activity in these cells.

Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study

“…Most patients with OA were taking analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, it is an unlikely explanation for the differences observed in our study, as NSAIDs, including aspirin and COX-2 inhibitors, tend to decrease Wnt signaling, at least in cancer cells [46,47]. Although we were careful to obtain samples apart from the fracture focus itself, the possibility of some regional changes in gene expression cannot be completely excluded.…”

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…Aspirin downregulates the constitutively active Wnt/b-catenin signaling in colorectal cancer cells by increasing the phosphorylation of b-catenin (92). Aspirin is also reported to induce the mitochondria/ caspase-3 apoptotic pathway, which is dependent on the Wnt/b-catenin signaling in mesenchymal stem cells (93).…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…9 This has been recapitulated in aspirin-treated colorectal cancer cell lines, in which phosphorylative deactivation of PP2A, induced by aspirin treatment, mediated dose-dependent decreases in Wnt/b-catenin pathway activation. 10 Recent studies in pancreatic cancer and colorectal cancer cell lines have suggested that the positive feedback of PP2A on Wnt/b-catenin signaling may be specific to transformed tumor cells and be essential for maintenance of active Wnt signaling. 11,12 PP2A is essential for apoptosis in cells with functional Bcl2.…”