Inhibition of cathepsin S confers sensitivity to methyl protodioscin in oral cancer cells via activation of p38 MAPK/JNK signaling pathways.
Oral cancer is one of the most common cancers in the world. Approximately 90% of oral cancers are subtyped to oral squamous cell carcinoma (OSCC). Despite advances in diagnostic techniques and improvement in treatment modalities, the prognosis remains poor. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. Methyl protodioscin (MP) is a furostanol bisglycoside with a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. The aim of the present study was to determine the antitumor activity of MP on OSCC and its underlying mechanisms. Our results show that treatment of OSCC cells with MP potently inhibited cell viability. Moreover, MP leading to cell cycle arrest at G2/M phase, which subsequently activates caspase-3, -8, -9 and PARP to induce cell apoptosis. Meanwhile, we also demonstrate that MP induces a robust autophagy in OSCC cells. The results indicate cathepsin S (CTSS) is involved in MP-induced apoptosis and autophagy by modulation of p38 MAPK and JNK1/2 pathways. These findings may provide rationale to combine MP with CTSS blockade for the effective treatment of OSCC.
Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan.|School of Optometry, Chung Shan Medical University, Taichung, 40201, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.
Ming-Ju
MJ
Hsieh
Institute of Oral Sciences, Chung Shan Medical University, Taichung, 40201, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan.
Chiao-Wen
CW
Lin
Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, 500, Taiwan.
Mu-Kuan
MK
Chen
Department of Pharmacy, Changhua Christian Hospital, Changhua, 500, Taiwan.|College of Health Sciences, Chang Jung Christian University, Tainan, 71101, Taiwan.|Department of Recreation and Holistic Wellness, Mingdao University, Changhua, 52345, Taiwan.
Su-Yu
SY
Chien
Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan.
Yu-Sheng
YS
Lo
Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan.
Yi-Ching
YC
Chuang
Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan.
Yi-Ting
YT
Hsi
Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan.
Chia-Chieh
CC
Lin
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 600, Taiwan.
Jui-Chieh
JC
Chen
Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
Shun-Fa
SF
Yang
D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*
D012503:Saponins; C425324:methyl protodioscin; D002403:Cathepsins; C028217:cathepsin S; D004144:Diosgenin