Flaxseed Consumption Inhibits Chemically-induced Lung Tumorigenesis andModulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/JMice

Flaxseed consumption is associated with reduced oxidative stress and inflammation in lung injury models, and has shown anti-cancer effects for breast and prostate tissues. However, the chemopreventive potential of flaxseed remains unexplored for lung cancer. In this study, we investigated the effect of flaxseed on tobacco smoke carcinogen (NNK)-induced lung tumorigenesis in an A/J mouse model. Mice exposed to NNK were fed a control diet or a 10% flaxseed-supplemented diet for 26 weeks. Flaxseed-fed mice showed reduced lung tumor incidence (78%) and multiplicity, with an average of 2.7 ± 2.3 surface lung tumor nodules and 1.0 ± 0.9 H&E cross-section nodules per lung compared to the control group which had 100% tumor incidence and an average of 10.2 ± 5.7 surface lung tumor nodules and 3.9 ± 2.6 H&E cross-section nodules per lung. Further, flaxseed-fed mice had a lower incidence of adenocarcinomas compared to control-fed mice. Western blotting performed on normal lung tissues showed flaxseed suppressed phosphorylation (activation) of p-AKT, p-ERK, and p-JNK kinases. RNA-Seq data obtained from normal lung and lung tumors of control and flaxeed-fed mice suggested that flaxseed intake resulted in differential expression of genes involved inflammation-mediated cytokine signaling (IL-1,-6,-8,-9, and -12α), xenobiotic metabolism (several CYPs, GSTs, and UGTs), and signaling pathways (AKT and MAPK) involved in tumor cell proliferation. Together, our results indicate that dietary flaxseed supplementation may be an effective chemoprevention strategy for chemically-induced lung carcinogenesis by altering signaling pathways, inflammation, and oxidative stress.

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