Non-thermal plasma induces AKT degradation through turn-on the MUL1 E3 ligase in head and neck cancer
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Sun-Yong Kim1, Haeng-Jun Kim1,2, Sung Un Kang1, Yang Eun Kim1,2, Ju Kyeong Park1,2, Yoo Seob Shin1, Yeon Soo Kim1, Keunho Lee3, Chul-Ho Kim1,2
1Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea
2Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
3PSM America Inc., Colorado Springs, CO, USA
Chul-Ho Kim, e-mail: [email protected]
Keywords: non-thermal plasma (NTP), head and neck cancer (HNC), AKT ubiquitination, liquid type plasma (LTP), mitochondrial E3 ubiquitin protein ligase 1 (MUL1)
Received: June 23, 2015 Accepted: September 18, 2015 Published: September 30, 2015
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.
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