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Resolution of Eicosanoid/Cytokine Storm Prevents Carcinogen and Inflammation-Initiated Hepatocellular Cancer Progression

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Resolution of Eicosanoid/Cytokine Storm Prevents Carcinogen and Inflammation-Initiated Hepatocellular Cancer Progression Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression Anna Fishbeina,b,c,1, Weicang Wangd,e,1, Haixia Yanga,b,c,1, Jun Yangd,e,1, Victoria M. Halliseya,b,c,1, Jianjun Denga,b,c,1, Sanne M. L. Verheula,b,c, Sung Hee Hwangd,e, Allison Gartunga,b,c, Yuxin Wangd,e, Diane R. Bielenbergf, Sui Huangg, Mark W. Kieranh,i,2, Bruce D. Hammockd,e,1,3, and Dipak Panigrahya,b,c,1,3 aCenter for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; bDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; cCancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; dDepartment of Entomology and Nematology, University of California, Davis, CA 95616; eUniversity of California, Davis Comprehensive Cancer Center, University of California, Davis, CA 95616; fVascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115; gInstitute for Systems Biology, Seattle, WA 98109; hDivision of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; and iDepartment of Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115 Contributed by Bruce D. Hammock, June 11, 2020 (sent for review April 21, 2020; reviewed by Kenneth Honn and Ann C. Skulas-Ray) Toxic environmental carcinogens promote cancer via genotoxic trigger proinflammatory cytokines (e.g., TNF-α and IL-6) as well and nongenotoxic pathways, but nongenetic mechanisms remain as caspase activation, leading to apoptotic cell death of multiple poorly characterized. Carcinogen-induced apoptosis may trigger cell types, including hepatocytes, lymphocytes, splenocytes, mac- escape from dormancy of microtumors by interfering with inflam- rophages, and endothelial cells (16–18). AFB1 can also negatively mation resolution and triggering an endoplasmic reticulum (ER) impact the innate immune defense by impairing macrophage stress response. While eicosanoid and cytokine storms are well- functions, such as phagocytosis (19), a critical process in the res- characterized in infection and inflammation, they are poorly charac- olution of inflammation (15, 20, 21). terized in cancer. Here, we demonstrate that carcinogens, such as While environmental carcinogens can cause cancer, their aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell nongenotoxic mechanisms are not well understood. Cell death MEDICAL SCIENCES debris stimulates hepatocellular carcinoma (HCC) tumor growth via an (“debris”)-mediated hyperinflammation generated by cytotoxic “eicosanoid and cytokine storm.” AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress- drugs stimulates the growth of surviving tumor cells via a cyto- response genes including BiP, CHOP,andPDI in macrophages. Thus, kine storm of proinflammatory and proangiogenic mediators (14, selective cytokine or eicosanoid blockade is unlikely to prevent 15, 22, 23). Chronic inflammation and proinflammatory cyto- carcinogen-induced cancer progression. Pharmacological abrogation kines cause hyperplasia, oxidative stress, and act synergistically of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated Significance ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation Eicosanoid and cytokine storms are poorly characterized in resolution via dual COX-2/sEH inhibition is an approach to prevent cancer. Our study demonstrates the environmental carcinogen carcinogen-induced cancer. aflatoxin B1 (AFB1) promotes hepatocellular carcinoma (HCC) by triggering a debris-stimulated proinflammatory and proangio- cell death | carcinogenesis | soluble epoxide hydrolase | genic “eicosanoid and cytokine storm” in the tumor microen- inflammation resolution | bioactive lipid vironment. The dual COX-2/sEH inhibitor PTUPB prevents AFB1- stimulated HCC growth by increasing macrophage phagocyto- flatoxins, a group of natural carcinogens, represent one of sis of debris and suppressing the eicosanoid and cytokine Athe critical causes of hepatocellular carcinoma (HCC), the storm, thus promoting resolution of inflammation. Enhancing second leading cause of cancer mortality worldwide. Aflatoxin B1 endogenous clearance of debris via eicosanoid regulation, such (AFB1), a mycotoxin produced by Aspergillus fungi, is a con- as dual inhibition of COX-2/sEH, is a strategy to stifle inflam- taminant of a large portion of the world’s food supply, causing mation and thus suppress tumor progression driven by car- over 5 billion people to be at high risk for HCC (1, 2). Aflatoxins cinogens. sEH and dual COX-2/sEH inhibitors are in clinical may play a causative role in 4.6 to 28.2% of all HCC cases development for multiple inflammatory diseases and thus may worldwide (3). While AFB1-induced DNA damage mediates be rapidly translated for the prevention and treatment of carcinogen-induced cancers. HCC, AFB1-derived DNA adducts alone may not be sufficient to cause and promote HCC or predict its progression (4–6). In addition to DNA damage or DNA adduct formation, other key 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., characteristics of carcinogens include their ability to induce ox- 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 idative stress, promote chronic inflammation, be immunosup- D.P. wrote the paper. pressive, and stimulate angiogenesis (7–9). Aflatoxins are also Reviewers: K.H., Wayne State University; and A.C.S.-R., University of Arizona. cytotoxic and various types of cell death can induce lineage The authors declare no competing interest. switching of hepatocytes to produce HCC or intrahepatic chol- Published under the PNAS license. angiocarcinoma, supporting nongenetic mechanisms in tumori- 1A.F., W.W., H.Y., J.Y., V.M.H., J.D., B.D.H., and D.P. contributed equally to this work. genesis (10). HCC ensues in the presence of excessive hepatic 2Present address: Pediatric Oncology, Bristol-Myers Squibb, Lawrenceville, NJ 08648. apoptosis and nonresolving inflammation in the tumor micro- 3To whom correspondence may be addressed. Email: [email protected] or environment (10, 11). Apoptotic cell death stimulates production [email protected]. of tumor-promoting eicosanoids, including cyclooxygenase This article contains supporting information online at https://www.pnas.org/lookup/suppl/ (COX)-derived prostaglandins, through the arachidonic acid doi:10.1073/pnas.2007412117/-/DCSupplemental. pathway in the tumor microenvironment (12–15). Aflatoxins www.pnas.org/cgi/doi/10.1073/pnas.2007412117 PNAS Latest Articles | 1of12 Downloaded by guest on October 4, 2021 with DNA damage to drive mutations and carcinogenesis cancer and HCC progression (30, 31). AFB1-induced HCC is (24–27). Carcinogens induce reactive oxygen and nitrogen spe- suppressed by a potent antiinflammatory, synthetic triterpenoid, cies, resulting in oxidative stress and inflammation (28). Acti- which only partially reduces the AFB1 adduct burden (4). Acti- vation of the mitochondrial apoptotic pathway in hepatocytes vation of endogenous inflammation resolution programs counter- generates reactive oxygen species (ROS), leading to oxidative regulates a series of proinflammatory cytokines via clearance of damage and liver tumorigenesis (29). Inflammatory cells and debris (15, 20, 21, 32), eliminates micrometastases, and prevents cancer cells generate free radicals and soluble mediators, such as tumor recurrence (33). metabolites of arachidonic acid, cytokines, and chemokines, which Selective cytokine or eicosanoid pathway blockade by antiin- act by further producing reactive species (27). These mediators, flammatory agents, such as COX-2 selective inhibitors (coxibs), including proinflammatory cytokines (e.g., IL-6, CCL2/MCP-1, have resulted only in transient antiinflammatory and antitumor and TNF-α), are stimulated by carcinogens and correlate with activity in patients (34–41). Coxibs cause a shunting of arachi- poor patient survival. Neutralization of these proinflammatory donic acid metabolism to cytochrome P450 (CYP450) and lip- cytokines has been demonstrated to suppress carcinogen-induced oxygenase (LOX) pathways, which counteracts the antitumor Fig. 1. AFB1-generated cell death stimulates HCC via up-regulation of sEH and COX-2. Annexin V/PI analysis of (A) Hepa 1-6 murine and (B) HepG2 human HCC tumor cells treated with AFB1 (25 μM, 48 h) compared to vehicle. Quadrants containing dead tumor cells are outlined in pink. Bar graphs represent means of percent cell death ±SEM. n = 3 per group. **P < 0.01, ****P < 0.0001 vs. vehicle. (C) Hepa 1-6 tumor growth stimulated by AFB1-generated dead cells coinjected with a subthreshold inoculum of living cells. n = 5 to 15 mice per group. The two-tailed unpaired Student’s t test was used for final tumor 6 measurements throughout. *P < 0.05 vs. 10 living cells alone (no dead cells). (D) Percent survival of mice coinjected orthotopically into the liver with AFB1- generated Hepa 1-6 dead cells and a subthreshold inoculum of Hepa 1-6 living cells. n = 5 mice per group. Kaplan–Meier analysis indicated significantly shortened survival
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