Arctigenin suppresses unfolded protein response and sensitizes glucose deprivation-mediated cytotoxicity of cancer cells.
The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics.
Sun
Shengrong
S
Department of Breast and Thyroid Surgery, Wuhan University Renmin Hospital, Wuhan, China.
Wang
Xiong
X
Wang
Changhua
C
Nawaz
Ahmed
A
Wei
Wen
W
Li
Juanjuan
J
Wang
Lijun
L
Yu
De-Hua
DH
D051701:Activating Transcription Factor 4 / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D000071717:X-Box Binding Protein 1
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D017705:Lignans; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C018551:glucose-regulated proteins; D051701:Activating Transcription Factor 4; D005947:Glucose; C071942:arctigenin