Kim Hye-Young, Cho Yunhee, Kang HyeokGu, Yim Ye-Seal, Kim Seok-Jun, Song Jaewhan, Chun Kyung-Hee
Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Korea.
Department of Biochemistry, College of Life Science and Biotechnology, Seodaemun-gu, Seoul 03722, Korea.
Oncotarget. 2016 Aug 2;7(31):49902-49916. doi: 10.18632/oncotarget.10231.
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.
Wee1是丝氨酸/苏氨酸蛋白激酶家族的成员，是细胞周期进程的关键调节因子。已知WEE1在多种癌症中高表达并具有致癌功能，但尚未在胃癌中进行研究。在本研究中，我们调查了靶向WEE1在胃癌中的致癌作用和治疗潜力。首先，在IV期胃癌患者或伴有淋巴结转移的男性患者中确定了WEE1表达水平较高且生存概率较低。为了确定WEE1在胃癌细胞中的功能，我们发现WEE1缺失会降低胃癌细胞的增殖、迁移和侵袭能力，而WEE1的过表达则会增强这些作用。我们还通过一种小分子AZD1775（MK-1775）验证了靶向WEE1的临床应用，AZD1775是一种正在进行临床试验的WEE1特异性抑制剂。AZD1775显著抑制胃癌细胞的增殖并诱导其凋亡和细胞周期停滞，这在WEE1高表达的胃癌细胞中更有效。此外，我们在胃癌细胞和胃癌原位移植小鼠中进行了AZD1775与抗癌药物5-氟尿嘧啶或紫杉醇的联合治疗，以最大化AZD1775的治疗效果和安全性。联合治疗显著抑制了胃癌细胞的增殖和胃癌原位移植小鼠的肿瘤负荷。综上所述，我们提出WEE1过表达并可增强胃癌细胞的增殖和转移。因此，我们认为WEE1是胃癌治疗的有效靶点。
