Novel mechanism of ethaselen in poorly differentiated colorectal RKO cell growth inhibition: Simultaneous regulation of TrxR transcription, expression and enzyme activity.
Thioredoxin reductase (TrxR) is a ubiquitous intracellular redox enzyme that regulates tumor growth and proliferation in various cancer cells. Ethaselen (1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane), a novel anticancer agent, is designed to target mammalian TrxR1 with the aims of cancer growth inhibition and TrxR inactivation. In this study, we demonstrated that ethaselen significantly inhibits cell growth in the poorly differentiated colorectal RKO cell line, and simultaneously downregulates mammalian TrxR1 mRNA transcript levels, protein expression and enzyme activity, which differs from its actions in moderately differentiated colorectal LoVo cells. Ethaselen's significant abatement of the Wnt/beta-catenin cell differentiation-related signaling pathway was also observed in RKO cells; this apparently leads to its strong inhibitory effect on cell growth and TrxR1 activity in this cell line. These results suggest that ethaselen has a novel mechanism affecting cell growth in the poorly differentiated RKO colorectal cell line.
Yin
Hanwei
H
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Li
Jing
J
Xiong
Kun
K
Wang
Lihui
L
Wang
Tianyu
T
Tan
Qiang
Q
Fu
Jianing
J
Ren
Xiaoyuan
X
Zeng
Huihui
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation; D006801:Humans; D046228:Microarray Analysis; D016566:Organoselenium Compounds / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C478160:(1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016566:Organoselenium Compounds; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C529432:ethaselen-1; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1