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 G1-phase cell cycle arrest. Molecular studies revealed that EL decreased mRNA or protein expression levels of the G1-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 p21WAF1/CIP1, a negative regulator of the G1phase. The results suggest that EL inhibits the growth of NSCLC cell lines by downregulating G1-phase cyclins and CDKs, and upregulating p21WAF1/CIP1, which leads to G1-phase cell cycle arrest. Therefore, EL may hold promise as an adjuvant treatment for lung cancer therapy.
a Department of Biological Sciences , North Dakota State University , Fargo , North Dakota , USA.
Shireen
S
Chikara
a Department of Biological Sciences , North Dakota State University , Fargo , North Dakota , USA.
Kaitlin
K
Lindsey
a Department of Biological Sciences , North Dakota State University , Fargo , North Dakota , USA.
Harsharan
H
Dhillon
b Department of Plant Sciences , North Dakota State University , Fargo , North Dakota , USA.
Sujan
S
Mamidi
a Department of Biological Sciences , North Dakota State University , Fargo , North Dakota , USA.
Jeffrey
J
Kittilson
c Department of Medicine , University of Pennsylvania , Philadelphia , Pennsylvania , USA.
Melpo
M
Christofidou-Solomidou
a Department of Biological Sciences , North Dakota State University , Fargo , North Dakota , USA.
Katie M
KM
Reindl
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D016213:Cyclins; D017705:Lignans; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone