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Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer

Authors
 Hye-Young Kim  ;  Yunhee Cho  ;  HyeokGu Kang  ;  Ye-Seal Yim  ;  Seok-Jun Kim  ;  Jaewhan Song  ;  Kyung-Hee Chun 
Citation
 ONCOTARGET , Vol.7(31) : 49902-49916, 2016 
Journal Title
 ONCOTARGET 
Issue Date
2016
MeSH
Animals ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Cell Cycle ; Cell Cycle Proteins/metabolism* ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Female ; Fluorouracil/therapeutic use ; Humans ; Kaplan-Meier Estimate ; Lymphatic Metastasis ; Male ; Mice ; Mice, Nude ; Molecular Targeted Therapy* ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Nuclear Proteins/metabolism* ; Paclitaxel/therapeutic use ; Phenotype ; Prognosis ; Protein-Tyrosine Kinases/metabolism* ; Pyrazoles/therapeutic use ; Pyrimidines/therapeutic use ; Stomach Neoplasms/genetics* ; Stomach Neoplasms/therapy*
Keywords
5-FU ; AZD1775 (MK-1775) ; Paclitaxel ; WEE1 ; gastric cancer
Abstract
Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis. To determine the function of WEE1 in gastric cancer cells, we determined that WEE1 ablation decreased the proliferation, migration, and invasion, while overexpression of WEE1 increased these effects in gastric cancer cells. We also validated the clinical application of WEE1 targeting by a small molecule, AZD1775 (MK-1775), which is a WEE1 specific inhibitor undergoing clinical trials. AZD1775 significantly inhibited cell proliferation and induced apoptosis and cell cycle arrest in gastric cancer cells, which was more effective in WEE1 high-expressing gastric cancer cells. Moreover, we performed combination treatments with AZD1775 and anti-cancer agents, 5- fluorouracil or Paclitaxel in gastric cancer cells and in gastric cancer orthotopic-transplanted mice to maximize the therapeutic effect and safety of AZD1775. The combination treatments dramatically inhibited the proliferation of gastric cancer cells and tumor burdens in stomach orthotopic-transplanted mice. Taken together, we propose that WEE1 is over-expressed and could enhance gastric cancer cell proliferation and metastasis. Therefore, we suggest that WEE1 is a potent target for gastric cancer therapy.
DOI
10.18632/oncotarget.10231
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Jun(김석준)
Kim, Hye Young(김혜영)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151706
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