Meme Kanseri Hücre Hattında COX2 İnhibitörü İlaçların İnflamazom Aktivasyonu Üzerine Etkisinin Araştırılması
Project no. 22969 · Status: Kapanmış · 2021
Summary
<p>Chronic inflammation is thought to play a role in breast cancer prognosis. Inflammation has become a promising target for cancer prevention and treatment because it is closely related with tumor initiation, progression and metastasis. A number of mechanisms play a role in the initiation and maintenance of inflammation. The pyrin domain-containing NOD-like receptor 1 (NLRP1) inflammasome is responsible for the initiation of inflammation and the release of inflammatory cytokines such as IL-1β via caspase-1. Cyclooxygenase-2 (COX-2) is an enzyme induced by inflammatory stimuli and contributes to the pathogenesis of inflammation-related diseases. A positive association between COX-2 and NLRP1 inflammasome in breast cancer incidence, tumor size and metastasis has been demonstrated. However, the role of COX-2 in NLRP1 activation is still uncertain. In our project, the therapeutic mechanisms of two COX-2 inhibitors celecoxib and nimesulide in breast cancer were investigated via NLRP1 inflammasome activation. Celecoxib and nimesulide significantly reduced the viability of MDA-MB-231 cells and inhibited the colony-forming and migration of cells. In addition, both drugs caused a significant decrease in the secretion of the proinflammatory cytokine IL-1β and caspase-1 activity. Celecoxib decreased the amount of NLRP1 and caspase-1 protein levels. The same effect was not observed in gasdermin and caspase-5 proteins. Our results showed that the inhibition of NLRP1 activation may be important for cytotoxic effect of celecoxib. Nimesulide, has no inhibitory effect on protein components involved in NLRP1 inflammasome activation. However, the decrease in the activity of caspase-1 and levels of effector protein IL-1β indicate that cytotoxic effect of nimesulide may be mediated by a different pathway involving these two components. This project provided new information on the relationship between COX-2 inhibitors and NLRP1 activation in breast cancer therapy.</p><p><strong>Keywords:</strong> breast cancer, COX-2 inhibitors, inflammation, NLRP1 inflammasome</p>