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.
Kim
Ju-Young
JY
Department of Food Science and Biotechnology, Kyungnam University, Masan, Korea.
Hwang
Ji-Hwan
JH
Cha
Mi-Ran
MR
Yoon
Mi-Young
MY
Son
Eun-Soon
ES
Tomida
Akihiro
A
Ko
Bosung
B
Song
Si-Whan
SW
Shin-ya
Kazuo
K
Hwang
Yong-il
YI
Park
Hae-Ryong
HR
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