Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer
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Hye-Young Kim1,2, Yunhee Cho1,3, HyeokGu Kang1,3, Ye-Seal Yim1,3, Seok-Jun Kim1,3, Jaewhan Song2, Kyung-Hee Chun1,3
1Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Korea
2Department of Biochemistry, College of Life Science and Biotechnology, Seodaemun-gu, Seoul 03722, Korea
3Brain Korea 21 PlusProject for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Korea
Kyung-Hee Chun, email: [email protected]
Keywords: WEE1, AZD1775 (MK-1775), 5-FU, Paclitaxel, gastric cancer
Received: September 07, 2015 Accepted: May 28, 2016 Published: June 23, 2016
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.
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