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HSPA5 regulates signaling switch from pro-survival to pro-apoptosis through lysosome inhibition in head and neck cancer

Kim, Sun-Yong; Kim, Haeng-Jun; Kim, Yang Eun; Kim, Dae Ho; Lee, Yun Sang; Byeon, Hyung Kwon; Kim, Jang Hee; Lee, Keunho; Kim, Chul-Ho
Department of Otolaryngology
Non-thermal plasma (NTP) is an ionized gas and is considered as a new therapeutic tool for cancer. We have manufactured a liquid type of NTP (LTP) and successfully demonstrated its anti-cancer effects in head and neck cancer (HNC) in vitro and in vivo. Here, we identified the novel mechanism of LTP-induced cell death in HNC by inhibiting lysosome and endoplasmic reticulum (ER) stress-mediated autophagy through HSPA5 (also known as GRP78/BiP). LTP induced accumulation of cellular ubiquitinated proteins, which lead to ER stress-mediated autophagy. HSPA5 is an ER chaperone protein highly expressed in HNC patients frozen cancer tissues and a has pivotal role in LTP-induced ER stress, autophagy and cytotoxicity. LTP-induced HNC cytotoxicity was delayed 8 hours; however, HNC cells underwent death followed by strong accumulation of GFP-MAP1LC3 puncta. Particularly, LTP turned-on the apoptosis through mitochondrial membrane potential (MMP) reduction and lysosome activity downregulation via inducing of decreased level of lysosome-related proteins, such as transcription factor EB (TFEB), lysosome-associated membrane protein 1 (LAMP1), cathepsin D (CTSD), and cathepsin L (CTSL), and LTP-induced these cellular events were inhibited by HSPA5 overexpression. LTP strongly inhibited progression of HNC in a xenograft model, increased levels of ER stress/autophagy-related proteins, cleaved caspase 3, and decreased HSPA5 and p-AKT expression. These data suggest that HSPA5 negatively regulates HNC progression by shifting signaling from pro-survival via ER stress-mediated autophagy to apoptosis. Therefore, HSPA5 could be a therapeutic target for HNC using LTP, and LTP may be a beneficial candidate tool for HNC therapy.
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