Transforming Growth Factor-beta (TGF-b) plays a dual role in the progression of cancer. In the early stages of tumour development, TGF-b plays an important role in tumour suppression by preventing cellular differentiation and proliferation of cancer cells (1). However, TGF-b can evolve toward a tumour promoting profile, subsequently inducing epithelial to mesenchymal transition (EMT), suppressing the tumour immune response, and increasing cellular proliferation (1). Understanding the factors that trigger this transition, and how we may prevent them, is critical for the development of more effective immunotherapies.
Recent research has implicated the selective COX-2 inhibitor (Celecoxib) in the prevention of TGF-b induced EMT in both lung and bladder cancer (2, 3). This research highlights COX-2 as a potential target for the prevention, and potential reversal, of the EMT process.
However, additional research into the effects of Celecoxib has shown that it may also be inhibiting the 5-LOX pathway, thus introducing the question of whether the EMT preventative effects seen are from COX-2 or 5-LOX inhibition (4). This is a key point that must be studied as 5-LOX activity is essential for many immune processes, such as Natural Killer cell cytotoxicity and Dendritic cell homing (5, 6).
In this study, we aim to evaluate the effects of multiple selective COX-2 inhibitors on TGF-b induced EMT, as well as their effects on 5-LOX expression and activity to determine their true downstream effects. We hypothesise that the use of Celecoxib will reduce 5-LOX activity in cancer cells, natural killer cells, and dendritic cells. Additionally, we hypothesise that this dual inhibition of COX-2 and 5-LOX pathways will have reduced tumour suppressive efficacy, in comparison to targeted COX-2 inhibition.