목적: Recently, non-thermal plasma (NTP) has studied and reported as a novel cancer therapy method. However, the molecular mechanism of non-thermal plasma is unclear. Thus, we investigate that anti- cancer effect of non-thermal plasma through ubiquitination dependent proteasomal degradation of AKT. 방법:We analyzed the effects of non-thermal plasma (NTP) on cell death and the levels of AKT, p-AKT or MULAN, E3 ligase of p-AKT in head and neck cancer (HNC) cell lines. We also investigated the expression of MULAN and AKT in the specimens of HNC patients. For in vivo study, syngeneic xenograpft model by C3H/HeJ mouse were used. Plasma-conditioned medium (PCM), a liquid type of NTP was treated every day for 1 week and then, anti-cancer effect was analyzed by measuring of tumor volume or weight. We also determined of non-thermal plasma effect by Western blot used by tumor tissue. 결과:NTP induces the death of HNC cell lines with inducing of AKT ubiquitin-proteasome system (UPS). Specially, MUL1, an E3 ligase of AKT, gene expression was increased by NTP and NTP-induced HNC death was prevented by MUL1 siRNA. In addition, MUL1 was suppressed in HNC cancer patient tissues. We manufactured and generated PCM, also showed similar biological effects compared with direct treatment of NTP. In syngeneic xenograft tumor models, NTP was inhibited tumor progression through induced increased revel of MUL1 and decreased AKT level. 결론:Our results indicate that non-thermal plasma inhibits the development of tumor in vitro or in vivo model through the AKT ubiquitin dependent proteasomal degradation by MUL1. Therefore, these data imply that non-thermal plasma has therapeutic potential for use in a single or combination therapy for HNC.