Inhibition of LTA4H by bestatin in human and mouse colorectal cancerResearch in context
Simin Zhao,
Ke Yao,
Dan Li,
Kangdong Liu,
Guoguo Jin,
Mingyang Yan,
Qiong Wu,
Hanyong Chen,
Seung Ho Shin,
Ruihua Bai,
Gangcheng Wang,
Ann M. Bode,
Ziming Dong,
Zhiping Guo,
Zigang Dong
Affiliations
Simin Zhao
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America; Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, PR China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China; Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China
Ke Yao
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China
Dan Li
Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
Kangdong Liu
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, PR China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China; Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China
Guoguo Jin
The Henan Orthopedic Hospital, Zhengzhou, Henan, PR China
Mingyang Yan
China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China
Qiong Wu
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, PR China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China
Hanyong Chen
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America
Seung Ho Shin
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America
Ruihua Bai
Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
Gangcheng Wang
Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
Ann M. Bode
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America
Ziming Dong
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, PR China; Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China; Correspondence to: Z. Dong, Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450001, PR China.
Zhiping Guo
The Henan Orthopedic Hospital, Zhengzhou, Henan, PR China; Correspondence to: Z. Guo, The Henan Orthopedic Hospital, 100 Yongping Road, Zhengzhou, Henan 450001, PR China.
Zigang Dong
The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China; Correspondence to: Z. Dong, The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States of America.
Background: Our preclinical data showed that the leukotriene A4 hydrolase (LTA4H) pathway plays a role in colorectal cancer (CRC). High expression of LTA4H and leukotriene B4 receptor type 1 (BLT1) were also associated with CRC survival probability. Clinical samples were evaluated to determine whether LTA4H could serve as a therapeutic target and whether leukotriene B4 (LTB4) could be used as a biomarker for evaluating the efficacy of bestatin in CRC. Methods: Patients with Stage I-III CRC did or did not receive bestatin prior to surgery. Evaluable pairwise CRC patient blood samples were collected to evaluate LTB4 concentration. Tissues were processed by immunohistochemistry to detect the LTA4H pathway and Ki-67 expression. We also determined whether LTA4H or BLT1 was associated with CRC survival probability and explored the mechanism of bestatin action in CRC. Findings: Samples from 13 CRC patients showed a significant decrease in LTB4, the LTA4H signaling pathway, and Ki-67 in the bestatin-treated group compared with the untreated group. LTA4H and BLT1 are overexpressed in CRC and associated with CRC survival probability. Bestatin effectively inhibited LTB4 and tumorigenesis in the ApcMin/+ and CRC patient-derived xenograft mouse model. Interpretation: These results demonstrate that LTB4 could serve as a biomarker for evaluating bestatin efficacy in CRC and the antitumor effects of bestatin through its targeting of LTA4H and support further studies focusing on LTA4H inhibition in CRC. Keywords: Bestatin, LTA4H, LTB4, BLT1, Colorectal cancer
