Int J Biol Sci. 2019 Jan 1;15(2):312-324. doi: 10.7150/ijbs.29135.

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

Jixian Xiong1, 2§*, Shaoxiang Wang, Tie Chen, Xingsheng Shu, Xianming Mo3*, Gang Chang1, Jia-Jie Chen 1, 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, Chengdu610041, China

* Correspondence:

Jixian Xiong, PhD, School of Medicine, Shenzhen University, Xueyuan Ave 1066, Shenzhen, Guangdong 518055, China

E-mail: xiongjixian@szu.edu.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: xmingmo@scu.edu.cn; Telephone/Fax: +86-028-85164017

  • These authors contribute equally to this work.

 

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 protein expression during the sphere-forming growth of GCSC. 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 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. The study suggests that clusterin is critical for sustaining GCSC survival, a promising drug target in suppressing GCSC population in gastric cancer. Moreover, the study provides drug used in photodynamic therapy, VP, was able to effectively inhibit clusterin expression in GCSC, suppressed the viability of GCSC and indered the growth of GCSC xenografted tumor in mice, thus 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.

PMID: 30745823

 

Summary 

Gastric cancer is the fifth most common and the third most lethal cancer worldwide. The current therapeutic approach is surgery followed by chemotherapy and/or radiotherapy. However, the survival rate for advanced GC remains low. Most post-treatment deaths of patients are due to the recurrence accompanied by metastasis.

Cancer stem cell has been implicated in cancer relapse and metastasis which may be caused by CSC’s capacity in uncontrolled growth, resistance to chemo- and radiotherapies. GCSC-targeting therapies are currently being investigated, including chemotherapeutic and biological agents that targeting GCSC surface markers, signaling pathways, the CSC microenvironment, and others. However, few agents against these molecules can efficiently eliminate GCSC, which leads to relapse, chemoresistance, and treatment failure. Therefore, finding the key molecule(s) involved in GCSC survival, and developing the targeting drugs are crucial for GCSC-targeting therapies.

We identified that clusterin is required for GCSC survival via modulating HSP90 function. We also discovered that verteporfin (VP), a FDA approved drug, was able to effectively inhibit clusterin expression in GCSC, suppress the viability of GCSC and inder the growth of GCSC xenografted tumor in mice.

Our findings suggested that lusterin is a promising drug target in suppressing GCSC population in gastric cancer and consequently attenuating malignancy exerted by GCSC in patients. Importantly, our findings provided us a drug, VP, which is already being approved for treating neovascular macular degeneration, can prevent recurrence and/or metastasis mediated by GCSC in GC patients by targeting clusterin (Figure 1). This manuscript provides exciting evidence that clusterin-targeted therapy as well as VP treatment in combination with or subsequent to conventional chemotherapy for slowing down or stopping the spreading of GC to other vital organs which is the major cause of mortality in GC.

 

 

 

Figure 1. Schematic diagram illustrated that VP inhibits tumor growth and malignant development by targeting clusterin. Clusterin, is critical for the survival of GCSC (depicted in red) which gives rises to progressive gastric cancer. Treatment with verteporfin will destroy the gastric cancer stem cells and induce tumor regression, prevent recurrence and/or metastasis mediated by GCSC.