Ablation of 5-lipoxygenase mitigates pancreatic lesion development

Lawrence M. Knab; Michelle Schultz; Daniel R. Principe; Windel E. Mascarinas; Elias Gounaris; Hidayatullah G. Munshi; Paul J. Grippo; David J. Bentrem

doi:10.1016/j.jss.2014.10.021

Ablation of 5-lipoxygenase mitigates pancreatic lesion development

Lawrence M. Knab^*, Michelle Schultz, Daniel R. Principe, Windel E. Mascarinas, Elias Gounaris, Hidayatullah G. Munshi, Paul J. Grippo, David J. Bentrem

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and methods Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO^-/-) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO^+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO^-/- mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO^+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO^-/- mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.

Original language	English (US)
Pages (from-to)	481-487
Number of pages	7
Journal	Journal of Surgical Research
Volume	194
Issue number	2
DOIs	https://doi.org/10.1016/j.jss.2014.10.021
State	Published - Apr 1 2015

Funding

The authors gratefully acknowledge the contribution of Carolyn Pelham and Kevin Adrian for their outstanding care and oversight of mice for the duration of this diet study. The research described herein was generously supported by funds provided by the Barnum Foundation and Zell Family Foundation at Northwestern University , the Nathan and Isabel Miller Family Foundation , the IDP Foundation , National Institutes of Health R21 CA123041-01 (P.J.G.), and National Institutes of Health R01 CA161283-01 (P.J.G.).

Keywords

5-Lipoxygenase
Inflammation
Omega-6 fatty acids
Pancreatic cancer

ASJC Scopus subject areas

Surgery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jss.2014.10.021

Cite this

@article{83bcd6389b4e42a0be7227bfa51129b5,

title = "Ablation of 5-lipoxygenase mitigates pancreatic lesion development",

abstract = "Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and methods Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO-/-) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO-/- mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO-/- mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.",

keywords = "5-Lipoxygenase, Inflammation, Omega-6 fatty acids, Pancreatic cancer",

author = "Knab, {Lawrence M.} and Michelle Schultz and Principe, {Daniel R.} and Mascarinas, {Windel E.} and Elias Gounaris and Munshi, {Hidayatullah G.} and Grippo, {Paul J.} and Bentrem, {David J.}",

year = "2015",

month = apr,

day = "1",

doi = "10.1016/j.jss.2014.10.021",

language = "English (US)",

volume = "194",

pages = "481--487",

journal = "Journal of Surgical Research",

issn = "0022-4804",

publisher = "Academic Press Inc.",

number = "2",

}

TY - JOUR

T1 - Ablation of 5-lipoxygenase mitigates pancreatic lesion development

AU - Knab, Lawrence M.

AU - Schultz, Michelle

AU - Principe, Daniel R.

AU - Mascarinas, Windel E.

AU - Gounaris, Elias

AU - Munshi, Hidayatullah G.

AU - Grippo, Paul J.

AU - Bentrem, David J.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and methods Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO-/-) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO-/- mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO-/- mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.

AB - Background Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. Materials and methods Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO-/-) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO+/+ mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. Results Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO-/- mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO+/+ mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO-/- mice. Conclusions The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.

KW - 5-Lipoxygenase

KW - Inflammation

KW - Omega-6 fatty acids

KW - Pancreatic cancer

UR - http://www.scopus.com/inward/record.url?scp=84924862866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924862866&partnerID=8YFLogxK

U2 - 10.1016/j.jss.2014.10.021

DO - 10.1016/j.jss.2014.10.021

M3 - Article

C2 - 25454978

AN - SCOPUS:84924862866

SN - 0022-4804

VL - 194

SP - 481

EP - 487

JO - Journal of Surgical Research

JF - Journal of Surgical Research

IS - 2

ER -

Ablation of 5-lipoxygenase mitigates pancreatic lesion development

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this