title: Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.
abstract: Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. Here, we show that compound C (also known as dorsomorphin), a small-molecule inhibitor of AMP-activated protein kinase (AMPK) and bone morphogenetic protein (BMP) signaling, inhibit the UPR-induced transcription program depending on the glucose deprivation conditions. We found that compound C prevented UPR marker glucose-regulated protein 78 (GRP78) accumulation and exerted enhanced cytotoxicity during glucose deprivation. Gene expression profiling, together with biochemical analysis, revealed that compound C had a unique mode of action to suppress the transcriptional activation of UPR-targeted genes, as compared with the classic UPR inhibitors versipelostatin and biguanides. Surprisingly, the UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. We further found that combination treatments of compound C and the classic UPR inhibitors resulted in synergistic cell death with UPR suppression during glucose deprivation. Our findings demonstrate that compound C could be a unique tool for developing a UPR-targeted antitumor therapy.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Saito
authors.forename: Aki
authors.initials: A
authors.lastname: Furuno
authors.forename: Junko
authors.initials: J
authors.lastname: Sakurai
authors.forename: Hae-Ryong
authors.initials: HR
authors.lastname: Park
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D001645:Biguanides / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose / Q000172:deficiency*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009844:Oligosaccharides / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D001645:Biguanides; D019485:Bone Morphogenetic Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018942:Macrolides; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; C053387:endoplasmin; C490154:versipelostatin; C516138:dorsomorphin; D000263:Adenylate Kinase; D005947:Glucose