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.
Bibliographical noteFunding Information:
This work was supported by the Hormel Foundation and National Institutes of Health grants CA187027 , CA166011 , and CA196639 . This work was supported by China Scholarship Council .
The authors thank Todd Schuster for supporting experiments and Tara Adams for supporting animal experiments. This work was supported by the Hormel Foundation and National Institutes of Health grants CA187027, CA166011, and CA196639. This work was supported by China Scholarship Council. The authors declare no conflicts of interest. S.M.Z. Z.M.D. and Z.D. designed the study. S.M.Z. K.Y. and K.D.L. performed, acquired and analyzed the data. Z.P.G. D.L. G.G.J. G.C.W. and R.H.B. provided blood and tissues from colon cancer patients. M.Y.Y. and Q.W. performed some experiments. S.M.Z. K.Y. and A.M.B. wrote paper. S.M.Z. K.Y. and S.H·S revised the paper.
- Colorectal cancer