Cold atmospheric plasma targets triple negative breast cancer cells via SCAF11-mediated competitive protein degradation and synergizes with miRNA-146b-5p

Cold atmospheric plasma (CAP), a redox-regulatory tool, has demonstrated its potency in selectively arresting a wide range of cancer cells, yet its molecular mechanism remains elusive that has largely hindered its clinical translation. Accumulating evidence has implicated the role of CAP in attenuating chronic inflammation in multiple diseases. Using triple negative breast cancer, which is short of effective therapies with little adverse effect, as the tumor model, we reported a synergistic approach to enhance the anti-cancer efficacy of CAP both in vitro and in vivo by coupling it with the mimics of miRNA-146b-5p, a known negative regulator of multiple inflammatory genes in diversified types of cells. Moreover, we identified an innovative path leading to CAP-enabled cancer death involving a SCAF11-mediated competition between FOXO1 and METTL14. This mechanistic model caused enhanced FOXO1 protein degradation and increased pri-miRNA-146b-5p m⁶A methylation for miRNA-146b-5p maturation. Our findings novel in conceptually proposing a competitive ubiquitination mechanism between two proteins under insufficient E3 ligase supply, and a combinatorial onco-therapeutic modality taking advantages of the unique benefits of CAP and miRNA mimics in alleviating chronic inflammation. Our results have also validated our hypothesis on the role of CAP in selectively targeting transformed cells via attenuating chronic inflammation.