Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity.
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 eIF2 alpha 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.
Department of Food Science and Biotechnology, Kyungnam University, Masan, Korea.
Ju-Young
JY
Kim
Ji-Hwan
JH
Hwang
Mi-Ran
MR
Cha
Mi-Young
MY
Yoon
Eun-Soon
ES
Son
Akihiro
A
Tomida
Bosung
B
Ko
Si-Whan
SW
Song
Kazuo
K
Shin-ya
Yong-il
YI
Hwang
Hae-Ryong
HR
Park
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D017705:Lignans; D005947:Glucose; C071942:arctigenin