Thioredoxin-like proteins as mediators of formaldehyde toxicity and their role in cancer

CARLA UMANSKY; AGUSTÍN MORELLATO; LUCAS PONTEL

Congreso; Annual reunion of the Argentinean Biosciences Societies SAIC, SAI AAFE, NANOMEd; 2021

Sociedad Argentina de Investigación Clínica

Formaldehyde (FA) is a mutagen and a carcinogen also produced inside cells as a byproduct of essential biological processes such as epigenetic demethylations and the one carbon cycle. We have previously shown that FA toxicity can not only be inflicted by damaging the DNA but also through the accumulation of reactive oxygen species.To further identify the mechanism by which FA is triggering cell death through oxidative stress, we searched for factors that are affected upon FA treatment. We found that the protein thioredoxin like-1 (TXNL1), which has been found associated with the 19S proteasome, is downregulated upon acute exposure to FA in HCT116 colorectal cancer cells. The protein level of TXNL1 drops 31.7±7.9% upon 5-h exposure to 200 uM FA, and 48.1±14.4% upon 5-h exposure to 400 uM FA as determined by western blot. On the other hand, chronic exposure to lower levels of FA does not significantly affect TXNL1 expression. In order to understand how TXNL1 is downregulated, we performed a bioinformatic analysis of the promoter region, which revealed an Antioxidant Response Element (ARE) site, suggesting the oxidative stress master regulator NRF2 might be involved in the control of TXNL1. In contrast to the canonical genes controlled by NRF2, the ARE site detected in the promoter of TXNL1 locates -7 pair bases upstream from TSS (Eukaryotic promoter database, p-value: 0.00001), suggesting that NRF2 might be directly repressing the expression of TXNL1 in response to FA. We explored The Cancer Genome Atlas Program (TCGA) database and found that TXNL1 is significantly more expressed in many cancer biopsies when compared to normal tissues. Moreover, we explored the GEPIA database and detected that reduced TXNL1 expression correlates with poor prognosis in colorectal cancer (p-value=0.04). This result suggests that downregulation of TXNL1 might increase aggressiveness of tumor cells.