Williams Cancer Institute

Exploring the Role of ALOX5 and Zileuton in Pancreatic Cancer Progression

5-Lipoxygenase (ALOX5) plays a crucial role in immune regulation. Currently, Zileuton is the only approved inhibitor of ALOX5. However, the specific mechanisms through which ALOX5 and Zileuton influence pancreatic cancer progression remain unclear. To address this, researchers investigated the effects of Zileuton on tumor-associated macrophage M2 polarization and pancreatic cancer invasion and metastasis, both in vivo and in vitro.

Through bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analyses, the study found a significant correlation between elevated ALOX5 levels and poor survival rates, advanced cancer stages, increased M2 macrophage infiltration, and the activation of the JAK/STAT pathways in macrophages. Clinical samples corroborated these findings, with immunofluorescence, quantitative real-time PCR, and immunohistochemical results confirming high ALOX5 expression in pancreatic cancer, primarily within macrophages.

Researchers constructed PANC-1 human pancreatic cancer cells and macrophages overexpressing ALOX5 using lentivirus. In PANC-1 pancreatic cancer cells, low-dose Zileuton inhibited cell invasion and migration by blocking ALOX5. In macrophages, ALOX5 induced an M2-like phenotype through the JAK/STAT pathway and enhanced macrophage chemotaxis towards PANC-1 cells. Zileuton was able to inhibit these effects, highlighting its potential therapeutic benefits.

The study also involved constructing a nude mouse model of in situ transplantation tumor of pancreatic cancer. Treatment with Zileuton resulted in increased survival rates and reduced liver metastasis in these mice, further demonstrating the drug’s efficacy.

These findings indicate that ALOX5 regulates tumor-associated macrophage M2 polarization via the JAK/STAT pathway, thereby promoting invasion and metastasis in pancreatic cancer. Zileuton can inhibit these effects by targeting ALOX5. This research provides a theoretical foundation for the potential use of Zileuton in pancreatic cancer treatment, suggesting that targeting ALOX5 with Zileuton could be a promising therapeutic strategy to improve patient outcomes.

By shedding light on the complex interactions between ALOX5 and the tumor microenvironment, this study paves the way for new approaches to treat pancreatic cancer, offering hope for more effective management of this aggressive disease.

Reference: Hu, W. M., Liu, S. Q., Zhu, K. F., Li, W., Yang, Z. J., Yang, Q., Zhu, Z. C., & Chang, J. (2023 Aug). The ALOX5 inhibitor Zileuton regulates tumor-associated macrophage M2 polarization by JAK/STAT and inhibits pancreatic cancer invasion and metastasis. https://pubmed.ncbi.nlm.nih.gov/37348233/

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