PDIA6 promotes the progression of ESCC via AKT1/mTOR signal pathway by forming disulfide-dependent TRAF4

Unveiling the underlying mechanism of esophageal squamous cell carcinoma (ESCC) is particularly valuable for discovering new therapeutic targets. The AKT1/mTOR pathway is a potential therapeutic pathway for ESCC. However, there has been limited investigation into sustaining constant activation of the AKT1/mTOR pathway. Here, we found that protein disulfide isomerase A6 (PDIA6), a protein disulfide isomerase, was highly expressed and negatively correlated with the survival of ESCC patients. PDIA6 promoted ESCC cell proliferation in vitro and in vivo . Mechanically, PDIA6 bound to tumor necrosis factor receptor-associated factor 4 (TRAF4) and catalyzed the formation of disulfide bonds at 39/42 and 83/106 sites to maintain TRAF4 stability by inhibiting SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) -mediated ubiquitination of TRAF4, resulting in the activating AKT1/mTOR signaling pathway. Notably, targeting PDIA6 with ASO treatment blocked the TRAF4/AKT1/mTOR signaling pathway, decreasing ESCC tumor growth. Therefore, PDIA6 can inhibit the AKT1/mTOR signaling pathway and retard ESCC progression. Our research highlights a novel mechanism for activating the AKT1/mTOR signaling pathway and provides a potential therapy strategy for ESCC.