<i>Fusobacterium nucleatum</i>’s Copper-FomA Proteins: Driving Cancer Forward

FomA is a major outer membrane protein of <i>Fusobacterium nucleatum</i> (Fn) overexpressed in colorectal cancer (CRC) tissues, where increased levels of Cu ions together with reactive oxygen species (ROS) were noted. In this comparative study, the connection between <i>Fn</i> surrounded by copper ions and the ROS overgeneration leading to the development of CRC is examined. Our study focused on a model peptide Ac-KGHGNGEEGTPTVHNEYH-NH₂ (<b>6L</b>) derived from the FomA reflecting a fragment of the protein loop no. 4, exposed to the external environment, which facilitates the binding of Cu ions. The coordination studies (potentiometric titration, UV-Vis, CD, EPR) showed that the <b>6L</b> bound Cu(II) and formed mono-, di-, and trinuclear complexes depending on the solution pH. The ability to generate ROS by promoting the Cu(III)/Cu(II)/Cu(I) redox cycle was proven by CV and EPR techniques. We also confirmed that upon adding Asc, the <b>6L</b> was fragmented and after copper coordination, the ROS production increased (e.g.,^•OH, ¹O₂, O₂^•-), leading to DNA damage. Stimulation of model mouse colon carcinoma cells by Cu(II) complex with <b>6L</b> demonstrated an abundant cellular ROS production, resulting in pronounced lipid peroxidation. Hypothetically, this action mode leads to the damage of colon cells and triggers carcinogenesis processes.