Abstract
Recent research on non-thermal plasma (NTP, an ionized gas) has identified it as a novel cancer therapeutic tool. However, the molecular mechanism remains unclear. In this study, we demonstrated NTP induced cell death of head and neck cancer (HNC) through the AKT ubiquitin-proteasome system. NTP increased the gene expression of mitochondrial E3 ubiquitin protein ligase 1 (MUL1), an E3 ligase for AKT, and NTP-induced HNC cell death was prevented by MUL1 siRNA. We also showed that MUL1 inhibited the level of AKT and p-AKT and MUL1 expression was increased by NTP-induced ROS. Furthermore, we optimized and manufactured a new type of NTP, a liquid type of NTP (LTP). In syngeneic and xenograft in vivo tumor models, LTP inhibited tumor progression by increasing the MUL1 level and reducing p-AKT levels, indicating that LTP also has an anti-cancer effect through the same mechanism as that of NTP. Taken together, our results suggest that NTP and LTP have great potential for HNC therapy.
Highlights
Non-thermal plasma (NTP) is an ionized gas composed of charged particles, electronically excited atoms and molecules, radicals, and UV photons [1]
The AKT kinase plays a role in cell survival, apoptosis, and head and neck cancer (HNC) development [8, 11], we investigated whether NTPinduced cell death correlates positively with the level of AKT
To explore whether NTP-induced reductions in AKT levels were associated with AKT kinase activity, we examined AKT kinase activity in NTP-treated cells using p-AKT specific-substrate (PAS) antibody
Summary
Non-thermal plasma (NTP) is an ionized gas composed of charged particles, electronically excited atoms and molecules, radicals, and UV photons [1]. We reported that NTP induced head and neck cancer (HNC) cell apoptosis by DNA damage via the ATM/p53 signaling pathway and cell death through mitogen-activated protein kinase-dependent mitochondrial reactive oxygen species (ROS) [5, 6]. The molecular mechanism of NTP-induced cancer cell death remains unclear. AKT is a well-known oncogenic kinase that plays a key role in cell survival, proliferation, apoptosis [8], and tumor development [9]. In relation to HNC, several studies reported the overexpression of AKT and the involvement of kinase activity in the lymph node metastasis of HNC patients [10, 11]. AKT plays a role in the development of HNC, the fifth most common cancer, its therapeutic efficiency for HNC through the inhibition of AKT remains unknown
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