## 4 Discussion
In addition, glycogen metabolism has shown to play an essential role in cancer cell survival [111]. We also observed upregulation of amino acid metabolism in 13-HPODE-treated cells, in particular glycine, serine, and threonine metabolism, which also plays a role in sustaining cancer cell survival. We also observed upregulation of _PHGDH_ involved in serine biosynthesis,which has also shown to maintain survival [112]. The significant impact of 13-HPODE on glycogen and amino acid metabolism of PDiff cells proposes a mechanism by which dietary LOOH may alter the metabolic processes of intestinal crypt or tumor cells to create an environment that initiates or promotes gut disease. Of note, intestinal crypt cells have the ability to initiate tumors especially if exposed to oxidative stress [113]. Components involved in physiological processes such as cell growth, differentiation, and motility were enriched in all three treatment groups. Among those were focal adhesion, cell-substrate junction, cell-cell junction, and cell leading edge. Previous reports indicated that oxidative stress including oxidized lipids could affect cellular barrier function through alteration of focal adhesion, adherens junction, and cell cytoskeleton [114; 115]. We also observed downregulation of _CLDN1_, which is a barrier-forming tight junction gene and upregulation of the pore-forming _CLDN2_ in 13-HPODE-treated cells, a characteristic of IBD [116]. In addition, it has been reported that LA and its oxidized metabolite could modulate cellular differentiation of Caco-2 cells [117; 118; 119]. PDiff Caco-2 cells showed downregulation of pathways involved in RNA processing and translation including ribosome and spliceosome as well as pyrimidine metabolism in the three treatment groups. This alteration might indicate reduced proliferation as these pathways have shown to be downregulated when Caco-2 cells lose their proliferative potential and shift towards differentiation [120]. In addition, induction of intestinal cell differentiation by 13-HPODE or LA has been previously reported [34; 121]. Alternatively, downregulation of the translation machinery could be due to oxidative damage to the ribosomes to which the cells needed a feedback inhibition of ribosome biogenesis to prevent translation errors and further ribosomal damage [122]. Of note, oxidative stress-induced modification of RNA has been linked to age-related diseases including neurodegenerative disorders [122]. Moreover, we observed increased expression of pro-apoptotic genes such as _DDIT4_, _BMF_, _BNIP3L_, and _BCL2L14_ and decreased expression of anti-apoptotic _BCL2L1_ in both 13-HPODE- and LA-treated groups suggesting reduced cell viability. This is consistent with previous studies reported that 13-HPODE increases cell death [6] and that LA induces apoptosis and cell differentiation [121] in Caco-2 cells. In addition, our results at the gene expression level showed downregulation of several genes involved in proliferation such as _CDK10_, _PIM1_, _CCNI/N2_, and _CYTOR_ in both 13-HPODE- and LA-treated cells, which suggests reduced proliferation. Although our results suggest, in part, that 13-HPODE promotes cell death, they may also indicate that 13-HPODE could trigger antioxidant response and modulate metabolic processes in a way that creates a carcinogenic environment and renders cells fight stress which could explain the resistance of some cancer types to anticancer therapies. 13-HPODE treatment of PDiff Caco-2 cells caused downregulation of oxidative phosphorylation. We observed downregulation of genes involved in electron transport chain complexes including complex I, III, IV, and V in 13-HPODE-treated cells. Our results support studies that demonstrated that oxidized LA products can damage the mitochondria and interfere with oxidative phosphorylation as these products can incorporate into mitochondrial membrane lipids and produce more radicals [123; 124].