title: Luteolin exerts a marked antitumor effect in cMet-overexpressing patient-derived tumor xenograft models of gastric cancer.
abstract: BACKGROUND
  Aberrated activation of cMet in gastric cancer contributes to tumor growth, angiogenesis and metastasis. cMet-overexpressing gastric cancer has a poor prognosis because of high tumor metastasis and limited therapeutic options. Luteolin is a common dietary flavonoid with antitumor properties. However, the antitumor effect of luteolin on cMet-overexpressing gastric cancer remain unclear.
  
  
  METHODS
  Two cMet-overexpressing patient-derived human tumor xenograft (PDTX) models of gastric cancer were established, and treated with luteolin or vehicle to evaluate the antitumor effects of luteolin. Tumor specimens were subjected to H&E staining and immunohistochemistry. MKN45 and SGC7901 cells that show high cMet expression were treated with varying concentrations of luteolin and evaluated by western blot, cell viability, apoptosis, migration, and invasion assays.
  
  
  RESULTS
  Luteolin inhibited the tumor growth in cMet-overexpressing PDTX models. Immunohistochemistry demonstrated that expression of cMet, MMP9 and Ki-67 were significantly down-regulated. Luteolin inhibited proliferation, promoted apoptosis and reduced the invasiveness of MKN45 and SGC7901 cells. Western blot revealed that luteolin promoted the activation of apoptosis-related proteins, caspase-3 and PARP-1, and down-regulated the invasion-associated protein, MMP9. Further studies demonstrated that luteolin decreased the expression and phosphorylation of cMet, and downstream phosphorylation of Akt and ERK. In addition, luteolin down-regulated phosphorylated Akt independently of cMet. Blocking Akt and/or ERK with the PI3K inhibitor, LY294002, or the ERK inhibitor, PD98059, induced down-regulation of MMP9 and up-regulation of cleaved caspase-3 and PARP-1, resembling the effects of luteolin.
  
  
  CONCLUSIONS
  Our findings ,for the first time, demonstrate that luteolin exerts marked antitumor effects in cMet-overexpressing PDTX models of gastric cancer, through a mechanism likely involving cMet/Akt/ERK signaling. These findings indicate that luteolin may act as a potential therapeutic option for cMet-overexpressing gastric cancer.
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. weedses@hotmail.com.
authors: Jun
authors: J
authors: Lu
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. fans_1988@163.com.
authors: Guangliang
authors: G
authors: Li
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. hekfeng@aliyun.com.
authors: Kuifeng
authors: K
authors: He
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. 15068117618@163.com.
authors: Weiqin
authors: W
authors: Jiang
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. 18858283440@126.com.
authors: Cong
authors: C
authors: Xu
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. yuqing@zju.edu.cn.
authors: Zhongqi
authors: Z
authors: Li
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. coldhot33@163.com.
authors: Haohao
authors: H
authors: Wang
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. wb_wang@126.com.
authors: Weibin
authors: W
authors: Wang
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. hywang98@gmail.com.
authors: Haiyong
authors: H
authors: Wang
authors: Department of Pathology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. 339251158@qq.com.
authors: Xiaodong
authors: X
authors: Teng
authors: Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. 11218203@zju.edu.cn.
authors: Lisong
authors: L
authors: Teng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047311:Luteolin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D019859:Proto-Oncogene Proteins c-met; D047311:Luteolin
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