Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression

Anna Fishbein; Weicang Wang; Haixia Yang; Jun Yang; Victoria M. Hallisey; Jianjun Deng; Sanne M. L. Verheul; Sung Hee Hwang; Allison Gartung; Yuxin Wang; Diane R. Bielenberg; Sui Huang; Mark W. Kieran; Bruce D. Hammock; Dipak Panigrahy

doi:10.1073/pnas.2007412117

Contributed by Bruce D. Hammock, June 11, 2020 (sent for review April 21, 2020; reviewed by Kenneth Honn and Ann C. Skulas-Ray)

Significance

Eicosanoid and cytokine storms are poorly characterized in cancer. Our study demonstrates the environmental carcinogen aflatoxin B₁ (AFB₁) promotes hepatocellular carcinoma (HCC) by triggering a debris-stimulated proinflammatory and proangiogenic “eicosanoid and cytokine storm” in the tumor microenvironment. The dual COX-2/sEH inhibitor PTUPB prevents AFB₁-stimulated HCC growth by increasing macrophage phagocytosis of debris and suppressing the eicosanoid and cytokine storm, thus promoting resolution of inflammation. Enhancing endogenous clearance of debris via eicosanoid regulation, such as dual inhibition of COX-2/sEH, is a strategy to stifle inflammation and thus suppress tumor progression driven by carcinogens. sEH and dual COX-2/sEH inhibitors are in clinical development for multiple inflammatory diseases and thus may be rapidly translated for the prevention and treatment of carcinogen-induced cancers.

Abstract

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 B₁ (AFB₁), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an “eicosanoid and cytokine storm.” AFB₁-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.

Footnotes

↵¹A.F., W.W., H.Y., J.Y., V.M.H., J.D., B.D.H., and D.P. contributed equally to this work.
↵²Present address: Pediatric Oncology, Bristol-Myers Squibb, Lawrenceville, NJ 08648.
↵³To whom correspondence may be addressed. Email: bdhammock{at}ucdavis.edu or dpanigra{at}bidmc.harvard.edu.

Author contributions: A.F., W.W., B.D.H., and D.P. designed research; A.F., W.W., H.Y., J.Y., V.M.H., J.D., S.M.L.V., S.H.H., Y.W., and D.R.B. performed research; A.F., W.W., S.H.H., A.G., S.H., M.W.K., and D.P. analyzed data; and A.F., W.W., A.G., S.H., M.W.K., B.D.H., and D.P. wrote the paper.
Reviewers: K.H., Wayne State University; and A.C.S.-R., University of Arizona.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2007412117/-/DCSupplemental.