Effect of lentivirus-mediated peroxiredoxins 6 gene silencing on the phenotype of human gastric cancer BGC-823 cells

Reactive oxygen species (ROS) are normal products of a number of biochemical reactions and are important signaling molecules. However, at the same time, they are toxic to cells and have to be strictly regulated by their antioxidant systems. The etiology and pathogenesis of many diseases are associated with increased ROS levels, and many external stress factors directly or indirectly cause oxidative stress in cells. Within this context, the overexpression of genes encoding the proteins in antioxidant systems seems to have become a viable approach to decrease the oxidative stress caused by pathological conditions and to increase cellular stress resistance. However, such manipulations unavoidably lead to side effects, the most dangerous of which is an increased probability of healthy tissue malignization or increased tumor aggression. The aims of the present review were to collect and systematize the results of studies devoted to the effects resulting from the overexpression of antioxidant system genes on stress resistance and carcinogenesis in vitro and in vivo. In most cases, the overexpression of these genes was shown to increase cell and organism resistances to factors that induce oxidative and genotoxic stress but to also have different effects on cancer initiation and promotion. The last fact greatly limits perspectives of such manipulations in practice. The overexpression of GPX3 and SOD3 encoding secreted proteins seems to be the “safest” among the genes that can increase cell resistance to oxidative stress. High efficiency and safety potential can also be found for SOD2 overexpression in combinations with GPX1 or CAT and for similar combinations that lead to no significant changes in H2O2 levels. Accumulation, systematization, and the integral analysis of data on antioxidant gene overexpression effects can help to develop approaches for practical uses in biomedical and agricultural areas. Additionally, a number of factors such as genetic and functional context, cell and tissue type, differences in the function of transcripts of one and the same gene, regulatory interactions, and additional functions should be taken into account.

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Tumoral Malignancy Decreases Coupled with Higher ROS and Lipid Peroxidation in HCT116 Colon Cancer Cells upon Loss of PRDX6

Lagal,

Montes-Osuna,

Ortiz-Olivencia

et al. 2024

Antioxidants

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Peroxiredoxin 6 (PRDX6) is an atypical member of the peroxiredoxin family that presents not only peroxidase but also phospholipase A2 and lysophosphatidylcholine acyl transferase activities able to act on lipid hydroperoxides of cell membranes. It has been associated with the proliferation and invasive capacity of different tumoral cells including colorectal cancer cells, although the effect of its removal in these cells has not been yet studied. Here, using CRISPR/Cas9 technology, we constructed an HCT116 colorectal cancer cell line knockout for PRDX6 to study whether the mechanisms described for other cancer cells in terms of proliferation, migration, and invasiveness also apply in this tumoral cell line. HCT116 cells lacking PRDX6 showed increased ROS and lipid peroxidation, a decrease in the antioxidant response regulator NRF2, mitochondrial dysfunction, and increased sensitivity to ferroptosis. All these alterations lead to a decrease in proliferation, migration, and invasiveness in these cells. Furthermore, the reduced migratory and invasive capacity of HCT116 cancer cells is consistent with the observed cadherin switch and decrease in pro-invasive proteins such as MMPs. Therefore, the mechanism behind the effects of loss of PRDX6 in HCT116 cells could differ from that in HepG2 cells which is coherent with the fact that the correlation of PRDX6 expression with patient survival is different in hepatocellular carcinomas. Nonetheless, our results point to this protein as a good therapeutic target also for colorectal cancer.

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Effect of lentivirus-mediated peroxiredoxins 6 gene silencing on the phenotype of human gastric cancer BGC-823 cells

Cited by 3 publications

References 22 publications

New insights into the roles of peroxiredoxins in cancer

New insights into the roles of peroxiredoxins in cancer

Effects of Antioxidant Gene Overexpression on Stress Resistance and Malignization In Vitro and In Vivo: A Review

Tumoral Malignancy Decreases Coupled with Higher ROS and Lipid Peroxidation in HCT116 Colon Cancer Cells upon Loss of PRDX6

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