Celecoxib suppresses colorectal cancer growth by inhibiting propionyl-CoA carboxylase alpha chain-mediated epithelial-mesenchymal transition and angiogenesis.

BACKGROUND: Celecoxib is widely used in the prevention and treatment of colorectal cancer (CRC). Although its mechanism of action involves both cyclooxygenase-2 (COX-2)-dependent and COX-2-independent pathways, the non-COX-2 targets of celecoxib remain poorly understood. Preliminary experiments revealed that celecoxib can inhibit the expression of the propionyl-CoA carboxylase alpha chain (PCCA); hence, this study aimed to investigate the role and underlying mechanisms of PCCA as a non-COX-2 target of celecoxib. METHODS: Wound-healing, transwell, and Cell Counting Kit-8 assays were conducted to evaluate the effects of celecoxib on migration, invasion, and proliferation in PCCA-overexpressing CRC cell lines. Western blotting was performed to assess the expression of epithelial-mesenchymal transition (EMT) markers. In vivo tumor growth and angiogenesis were examined by using mouse models. Quantitative polymerase chain reaction was used to analyse the transcriptional levels of placental growth factor (PLGF). RESULTS: Celecoxib inhibited PCCA expression in CRC and suppressed PCCA-mediated migration, invasion, and proliferation in COX-2-deficient CRC cell lines (HCT116 and DLD1). These effects were associated with the reversal of PCCA-induced downregulation of E-cadherin and upregulation of N-cadherin and vimentin. In addition, celecoxib inhibited PCCA-driven tumor growth and angiogenesis in HCT116 cells, which correlated with altered PLGF expression. CONCLUSION: Celecoxib suppresses PCCA-induced EMT and angiogenesis via a COX-2-independent mechanism. These findings suggest that celecoxib may offer additional therapeutic benefits for patients with CRC with elevated PCCA expression and reveal a novel potential antitumor mechanism of celecoxib.