期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：35
页码：21576-21587
DOI：10.1073/pnas.2007412117
出版社：The National Academy of Sciences of the United States of America
摘要：Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B 1 (AFB 1 ), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an “eicosanoid and cytokine storm.” AFB 1 -generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP , CHOP , and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.
