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Int J Biol Sci 2019; 15(2):312-324. doi:10.7150/ijbs.29135 This issue Cite

Research Paper

Verteporfin blocks Clusterin which is required for survival of gastric cancer stem cell by modulating HSP90 function

Jixian Xiong^1,2*✉, Shaoxiang Wang^1*, Tie Chen^1*, Xingsheng Shu^1*, Xianming Mo^3✉, Gang Chang¹, Jia-Jie Chen¹, Chenyang Li¹, Hui Luo¹, Jiing-Dwan Lee¹

1. School of Medicine, Shenzhen University, Shenzhen 518055, China
2. Shenzhen University International Cancer Center, Shenzhen University, Shenzhen 518055, China
3. Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
* These authors contribute equally to this work.

✉ Corresponding authors: Jixian Xiong, PhD, School of Medicine, Shenzhen University, Xueyuan Ave 1066, Shenzhen, Guangdong 518055, China. E-mail: xiongjixianedu.cn; Telephone/Fax: +86-755-86670623. Xianming Mo, PhD, Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. E-mail: xmingmoedu.cn; Telephone/Fax: +86-028-85164017 More

Abstract

Gastric cancer stem cell (GCSC) is implicated in gastric cancer relapse, metastasis and drug resistance. However, the key molecule(s) involved in GCSC survival and the targeting drugs are poorly understood. We discovered increased secreted clusterin (S-Clu) protein expression during the sphere-forming growth of GCSC via mass spectrometry. Overexpression of clusterin was detected in 69/90 (77%) of primary GC tissues and significantly associated with T stage, lymph node metastasis and TNM stage. Depletion of clusterin (Clu, the full-length intracellular clusterin) led to the declustering of GCSC tumorspheres and apoptosis of GCSC. Subsequently, we found clusterin was in complex with heat shock protein 90 beta (HSP90) and involved in regulating the cellular level of HSP90 client proteins. Furthermore, by screening a collection of drugs/inhibitors, we found that verteporfin (VP), a phototherapy drug, blocked clusterin gene expression, decreased the HSP90 client proteins and caused cell death of GCSC. VP treatment is more effective in eradicating GCSCs than in killing GC cells. Both clusterin silencing or VP treatment deterred tumor growth in human GCSC xenografts. These findings collectively suggest that GC patients can promptly benefit from clusterin-targeted therapy as well as VP treatment in combination with or subsequent to conventional chemotherapy for reducing mortality of GC.

Keywords: Gastric cancer stem cell, Clusterin, Verteporfin, HSP90

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