Enterolactone Induces G1-phase Cell Cycle Arrest in Nonsmall Cell Lung Cancer Cells by Downregulating Cyclins and Cyclin-dependent Kinases

Flaxseed is a rich source of the plant lignan secoisolariciresinol diglucoside (SDG), which is metabolized into mammalian lignans enterodiol (ED) and enterolactone (EL) in the digestive tract. The anticancer properties of these lignans have been demonstrated for various cancer types, but have not been studied for lung cancer. In this study, we investigated the anticancer effects of EL for several nonsmall cell lung cancer (NSCLC) cell lines of various genetic backgrounds. EL inhibited the growth of A549, H441, and H520 lung cancer cells in concentration- and time-dependent manners. The antiproliferative effects of EL for lung cancer cells were not due to enhanced cell death, but rather due to G(1)-phase cell cycle arrest. Molecular studies revealed that EL decreased mRNA or protein expression levels of the G(1)-phase promoters cyclin D1, cyclin E, cyclin-dependent kinases (CDK)-2, -4, and -6, and p-cdc25A; decreased phosphorylated retinoblastoma (p-pRb) protein levels; and simultaneously increased levels of p21(WAF1/CIP1), a negative regulator of the G(1) phase. The results suggest that EL inhibits the growth of NSCLC cell lines by downregulating G(1)-phase cyclins and CDKs, and upregulating p21(WAF1/CIP1), which leads to G(1)-phase cell cycle arrest. Therefore, EL may hold promise as an adjuvant treatment for lung cancer therapy.