Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin.

Abstract

OBJECTIVE:

To investigate the expression of 5-lipoxygenase (5-LOX) in metastatic prostate cancer and whether zileuton, the inhibitor of 5-LOX, plays a role in the metastasis of prostate cancer.

METHODS:

An enzyme-linked immunosorbent assay was used to measure 5-hydroxyeicosatetraenoic acid (5-HETE) in patient and TRAMP mice blood samples. Kaplan-Meier analysis and the log-rank test were used to analyze the survival of the mice. Immunofluorescence and immunohistochemistry were used to assay the expression of 5-LOX in the samples. After treatment with 10 μM zileuton, cell motility and the invasion of PC-3 cells were assayed using immunofluorescence, Western blotting, and transwell. TRAMP mice were treated with zileuton (600 mg/kg and 1200 mg/kg) at 24 weeks of age. Ten weeks later, the mice were killed, and the tumors (size and number) were measured.

RESULTS:

The levels of 5-HETE were significantly greater in the TRAMP mice with metastasis than in the tumors in situ. However, no such difference was found in the human samples. The lifespan of the mice was shorter at high levels of 5-HETE (>2.4 ng/mL). The expression of 5-LOX in the metastasis sample was notably greater than that in the tumors in situ. After treatment with zileuton, the expression of paxillin and E-cadherin in PC-3 and LNCaP cells was upregulated. In the transwell experiments, the motility of PC-3 was suppressed after treatment with zileuton. The mice treated with a high level of zileuton (1200 mg/kg) also had fewer tumors; however, the size did not show a significant difference.

CONCLUSION:

The inhibitor of 5-LOX, zileuton, can suppress prostate cancer metastasis by repaired expression of E-cadherin and paxillin.

• Authors: Zhe Meng, Rui Cao, Zhonghua Yang, Tao Liu, Yongzhi Wang, Xinghuan Wang
• Journal: Urology (Urology) Vol. 82 Issue 6 Pg. 1452.e7-14 (Dec 2013) ISSN: 1527-9995 [Electronic] United States
• PMID: 24295266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cadherins
• Hydroxyeicosatetraenoic Acids
• Lipoxygenase Inhibitors
• Paxillin
• 5-hydroxy-6,8,11,14-eicosatetraenoic acid
• Arachidonate 5-Lipoxygenase
• zileuton
• Hydroxyurea

Topics

• Animals
• Arachidonate 5-Lipoxygenase (drug effects, metabolism)
• Cadherins (metabolism)
• Cell Migration Assays
• Enzyme-Linked Immunosorbent Assay
• Humans
• Hydroxyeicosatetraenoic Acids (metabolism)
• Hydroxyurea (analogs & derivatives, pharmacology)
• Immunohistochemistry
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasm Metastasis (prevention & control)
• Paxillin (metabolism)
• Prostatic Neoplasms (pathology)
• Up-Regulation (physiology)