Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

• Published in: Life science alliance 2023-05, Vol.6 (5), p.e202201804
• Main Authors: Göbel, Tamara, Goebel, Bjarne, Hyprath, Marius, Lamminger, Ira, Weisser, Hannah, Angioni, Carlo, Mathes, Marius, Thomas, Dominique, Kahnt, Astrid S
• Format: Article
• Language: English
• Subjects: Arachidonate 5-Lipoxygenase - genetics; Colonic Neoplasms; Humans; Lipid Metabolism; Mechanistic Target of Rapamycin Complex 2; Phosphatidylinositol 3-Kinases
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202201804

The leukotriene (LT) pathway is positively correlated with the progression of solid malignancies, but the factors that control the expression of 5-lipoxygenase (5-LO), the central enzyme in LT biosynthesis, in tumors are poorly understood. Here, we report that 5-LO along with other members of the LT pathway is up-regulated in multicellular colon tumor spheroids. This up-regulation was inversely correlated with cell proliferation and activation of PI3K/mTORC-2- and MEK-1/ERK-dependent pathways. Furthermore, we found that and its target gene were involved in the repression of 5-LO during cell proliferation. Importantly, we found that this PI3K/mTORC-2- and MEK-1/ERK-dependent suppression of 5-LO is also existent in tumor cells from other origins, suggesting that this mechanism is widely applicable to other tumor entities. Our data show that tumor cells fine-tune 5-LO and LT biosynthesis in response to environmental changes repressing the enzyme during proliferation while making use of the enzyme under cell stress conditions, implying that tumor-derived 5-LO plays a role in the manipulation of the tumor stroma to quickly restore cell proliferation.