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.
Highlights
Glucose deprivation is a common feature of the solid tumor microenvironment and is caused by a combination of the poorly formed tumor vasculature, uncontrolled proliferation and abnormal energy metabolism of cancer cells
We first examined the effects of compound C on unfolded protein response (UPR) marker glucoseregulated protein 78 (GRP78) promoter activity in human fibrosarcoma HT1080 cells that were transiently transfected with the reporter gene plasmid pGRP78pro160-Luc [14]
Compound C suppressed GRP78 promoter activity induced by glucose withdrawal (Figure 1B), indicating that 2DG addition and glucose withdrawal were equivalent for compound C to exert UPR-inhibitory activity, the intensity of GRP78 induction was somewhat different between each of the stress condition
Summary
Glucose deprivation is a common feature of the solid tumor microenvironment and is caused by a combination of the poorly formed tumor vasculature, uncontrolled proliferation and abnormal energy metabolism of cancer cells. ATF6 becomes an active transcription factor by proteolytic cleavage [7,8], whereas IRE1 mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA, thereby converting it to a potent UPR transcriptional activator [9,10,11,12]. These transcription factors lead to coordinated induction of divergent UPR target genes, such as the ER-resident molecular chaperones glucose-regulated protein 78 and 94 (GRP78 and GRP94), for cell survival [13]
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