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Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity
Author(s) -
Kim JuYoung,
Hwang JiHwan,
Cha MiRan,
Yoon MiYoung,
Son EunSoon,
Tomida Akihiro,
Ko Bosung,
Song SiWhan,
Shinya Kazuo,
Hwang Yongil,
Park HaeRyong
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22085
Subject(s) - unfolded protein response , atf4 , apoptosis , integrated stress response , cancer research , cancer cell , chop , biology , chemistry , cancer , microbiology and biotechnology , biochemistry , gene , translation (biology) , messenger rna , genetics
Cancer cells in poorly vascularized solid tumors are constantly or intermittently exposed to stressful microenvironments, including glucose deprivation, hypoxia, and other forms of nutrient starvation. These tumor‐specific conditions, especially glucose deprivation, activate a signaling pathway called the unfolded protein response (UPR), which enhances cell survival by induction of the stress proteins. We have established a screening method to discover anticancer agents that could preferentially inhibit tumor cell viability under glucose‐deprived conditions. Here we identify arctigenin (ARC‐G) as an active compound that shows selective cytotoxicity and inhibits the UPR during glucose deprivation. Indeed, ARC‐G blocked expression of UPR target genes such as phosphorylated‐PERK, ATF4, CHOP, and GRP78, which was accompanied by enhanced phosphorylation of eIF2α during glucose deprivation. The UPR inhibition led to apoptosis involving a mitochondrial pathway by activation of caspase‐9 and ‐3. Furthermore, ARC‐G suppressed tumor growth of colon cancer HT‐29 xenografts. Our results demonstrate that ARC‐G can be served as a novel type of antitumor agent targeting the UPR in glucose‐deprived solid tumors. J. Cell. Physiol. 224:33–40, 2010 © 2010 Wiley‐Liss, Inc.