Colorectal cancer and arachidonic acid metabolism: state of the art in 2023.

By its very nature, the metabolism of arachidonic acid (AA) is a source of carcinogens: the peroxide intermediates prostaglandin (PG) G2 and PGH2 represent a potential source of free radicals, which are dangerous for the body because they can form adducts with DNA. Cyclooxygenase-2 (COX-2) is itself directly involved in the activation of certain environmental or dietary procarcinogens and in the metabolism of xenobiotics in non-hepatic tissues, which are responsible for the formation of carcinogens such as benzo[a]pyrene-7,8-diol-9,10-epoxide, thereby inducing DNA damage. COX-2 can also activate cellular proteins involved in tumour progression. PGE2 also influences the establishment of the tumour process via two pathways: activation of the PI3K/Akt cell survival pathway, and activation of growth factors stimulating the intervention of signalling pathways (Ras/MAPK, JAK/STAT). COX-2 appears to play an important role in the apoptosis process, since it is known that inhibition of COX-2 is correlated with an increase in the apoptotic process in many types of cancer. Several hypotheses have emerged as to the mechanisms implicating COX-2 in resistance to apoptosis. Firstly, inhibition of COX-2 has been linked to a concomitant increase in intracellular levels of arachidonic acid. Indeed, a high concentration of exogenous AA can induce apoptosis, independently of the formation of PGs. In HT-29 human colorectal cancer cells, AA accumulation leads to induction of the apoptotic process, notably via inhibition of Bcl-2. It is possible that COX-2 expression is increased in order to reduce the quantity of AA in the cell and prevent apoptosis. In addition, the action of COX-2 in carcinogenesis processes is also mediated by the biological effects of its metabolites. COX-2 induces the production of PGI2, which can bind and activate PPARδ. This suggests that inhibition of COX-2 leads to inhibition of PGI2 and inactivation of PPARδ, which is responsible for inhibiting the 14-3-3 protein. Bad would then be released from the latter to exert its pro-apoptotic effects. The binding of PGE2 to its specific receptors, such as EP1, EP2, EP3 and EP4, induces activation of survival pathways (Akt, ERK, etc.), an increase in Bcl-2 protein expression, and activation of the survival factor NF-κB, all of which can lead to resistance to apoptosis. COX-2 is known to be involved in the regulation of angiogenesis, the process of developing capillaries from pre-existing capillaries, in both healthy and tumour tissues. This phenomenon is involved in wound healing in particular, but also plays a role in tumour formation. The effects of COX-2 can appear via several pathways: increased expression of proangiogenic mediators such as VEGF (Vascular Endothelial Growth Factor) and bFGF (basic Fibroblast Growth Factor), stimulation of neovascularisation directly via the products of COX-2 activity (proangiogenic eicosanoids - thromboxane A2, PGE2 and PGI2) and inhibition of apoptosis in endothelial cells via stimulation of Bcl-2 and the Akt pathway. The physiological role of EP receptors in healthy tissues and cancerous tissues is determined by multiple factors such as cell type, the affinity of these receptors for their ligands and the parallel existence of other transduction pathways. EP receptors are involved in promoting carcinogenesis in colorectal cancer. In fact, they are capable of targeting a multitude of signalling pathways and of induce a PKA-dependent increase in VEGF, HIF-1α-dependent pathways, cfos, the PI3K/Akt pathway, the ERK pathway and β-catenin. The COX-2/PGE2 pathway also plays a role in cancer cell invasion and metastasis in many cancer types. Firstly, it has been shown that overexpression of COX-2 induces the synthesis of MMPs and therefore facilitates the mobility of tumour cells in the matrix. In addition, COX-2 induces a reduction in the expression of E-cadherin, explaining the inducing effect of COX-2 on the detachment of cancer cells, their passage and progression in the bloodstream or lymphatic network. Finally, PGE2 also plays an important role in tumour invasion. The role of the 4 types of PGE2 receptor in the formation of metastases has been studied. It has been shown that PGE2 can increase the number of metastases.