Understanding the role of Cysteinyl leukotriene receptor signaling in cancer progression and metastasis

Abstract

Background: Cysteinyl leukotrienes (cys-LTs) are pro-inflammatory mediators which enhance inflammation through cysteinyl leukotriene receptor 1 (CysLT1R) and cysteinyl leukotriene receptor 2 (CysLT2R). Although cys-LTs and their receptors are mainly implicated in asthma and inflammation, recent association of inflammation with cancer has led to enhanced interest in understanding these players in cancer progression and metastasis. However, the exact molecular mechanisms underlying key processes in cancer- proliferation, migration and invasion ( in vitro), tumor progression and metastasis (in vivo) by these mediators remain unexplored. Further, the contribution of these receptors in tumor vs stromal microenvironment, and their interactions is unknown. A thorough investigation of these receptor signaling can reveal their therapeutic potential in cancer progression and metastasis. Objective: To study how cysteinyl leukotriene receptors contribute to melanoma and breast cancer initiation, progression, and metastasis Methods: Expression and functional analysis of CysLTR was determined by transcript (qPCR), western blotting (protein) and by calcium flux assays. Cancer cell survival and proliferation were analyzed by XTT and BrDU assays. Activation of intracellular signaling molecules was determined by western blotting using phospho-specific antibodies. Migration and invasion were analyzed using trans-well assays. Tumors were induced in WT, Cysltr1-/- and Cysltr2-/- mice and their progression and metastasis were evaluated. Results: Breast cancer (EO771) and melanoma (Luc-B16F10-GFP) cells express high levels of CysLT2R compared to CysLT1R. Further, stimulation of tumor cells with cys-LTs caused phosphorylation of Erk, p38, JNK, Akt, and CREB independent of epidermal growth factor receptor (EGFR). Notably, treatment of tumor cells with CysLTR antagonists significantly reduced migratory capability of the cells suggesting the vital role played by CysLTRs in tumor cell migration. Finally, we observed a significant reduction in the tumor volume in mice deficient in CysLTR ( Cysltr1-/- and Cysltr2-/-) mice compared to the WT mice, indicating a role for CysLTR in mediating tumor growth in vivo. Conclusion: Cysteinyl leukotrienes play an important role in promoting tumor proliferation, and metastasis via CysLTR and therefore, understanding their signaling and targeting them can offer potential targets for cancer therapy. This work was supported by National Institutes of Health (R01AI144115 and R01HL148585) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.