Downregulation of cyclooxygenase‑1 stimulates mitochondrial apoptosis through the NF‑κB signaling pathway in colorectal cancer cells

Abstract

The prognosis of patients with colorectal cancer (CRC) remains poor owing to diagnosis typically occurring at advanced stages of the disease. The understanding of the molecular regulatory signatures of CRC may lead to the identification of biomarkers for the early detection, prevention and clinical intervention of CRC. Epidemiological studies have indicated that cyclooxygenase-1 (COX-1) serves an active function in colon carcinogenesis. However, the molecular mechanism underlying COX-1 regulation in CRC remains unknown. In the present study, COX-1 was identified to be markedly upregulated in colorectal tissues of patients with CRC, and in the CRC cell lines HCT116 and HT29. To determine the function of COX-1 in cancer development, short hairpin RNA knockdown of COX-1 was employed in HCT116 and HT29 CRC cells in the present study. The results demonstrated that silencing of COX-1 depolarized the mitochondrial membrane potential, inhibited adenosine triphosphate production, induced the generation of intracellular reactive oxygen species and triggered caspase-dependent mitochondrial apoptosis. Furthermore, depletion of COX-1 suppressed anti-apoptotic B-cell lymphoma 2 and enhanced pro-apoptotic Bcl-2-associated X protein expression by inhibiting the p65 subunit phosphorylation of nuclear factor κB (NF-κB). Taken together, the results of the present study indicated that COX-1 inhibition significantly triggered cell death by destroying the mitochondrial function that is associated with deactivation of the NF-κB signaling pathway. These results suggest COX-1 as a potential anticancer target in CRC.

Knockdown of Microtubule Associated Serine/threonine Kinase Like Expression Inhibits Gastric Cancer Cell Growth and Induces Apoptosis by Activation of ERK1/2 and Inactivation of NF-κB Signaling

“…NF-κB could upregulate levels of various genes that play a role in cell proliferation, migration and apoptosis [29,30] . NF-κB inactivation may also lead to mitochondriapathway-induced apoptosis in colon cancer cells by the way of inhibiting NF-κB/p65 phosphorylation [31,32] , block p65 phosphorylation at Ser536 and IκBα phosphorylation at Ser32, and therefore suppress NF-κB nuclear translocation in gastric cancer cells [33,34] . In addition, activation of ERK1/2 could either induce cell proliferation or apoptosis [35][36][37] .…”

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

“…COX enzymes have a role in response to oxidative stress, COX-1 is believed to play a constitutive housekeeping role [80] and its inhibition induce apoptosis and lead to Prostaglandin production induced by ionizing radiation [81]. In line with this, it has recently been demonstrated that downregulation of COX1 stimulates mitochondrial apoptosis through NH-kB signaling pathway [82].…”

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

“…COX enzymes have a role in response to oxidative stress, COX-1 is believed to play a constitutive housekeeping role [78] and its inhibition induce apoptosis and lead to Prostaglandin production induced by ionizing radiation [79]. In line with this, it has recently been demonstrated that downregulation of COX1 stimulates mitochondrial apoptosis through NH-kB signaling pathway [80].…”