Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation

Abstract

Glucose deprivation, a cell condition that occurs in solid tumors, activates the unfolded protein response (UPR). A key feature of the UPR is the transcription program activation, which allows the cell to survive under stress conditions. Here, we show that the UPR transcription program is disrupted by the antidiabetic biguanides metformin, buformin, and phenformin depending on cellular glucose availability. These drugs inhibit production of the UPR transcription activators XBP1 and ATF4 and induce massive cell death during glucose deprivation as did the antitumor macrocyclic compound versipelostatin. Gene expression profiling shows remarkable similarity in the modes of action of biguanides and versipelostatin determined by the broad range of glucose deprivation-inducible genes. Importantly, during glucose deprivation, most of the biguanide suppression genes overlap with the genes induced by tunicamycin, a chemical UPR inducer. Gene expression profiling also identifies drug-driven signatures as a tool for discovering pharmacologic UPR modulators. Our findings show that disrupting the UPR during glucose deprivation could be an attractive approach for selective cancer cell killing and could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors.

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

“…1B). In addition, 2DG is known to induce ER stress (19). We verified in CT26 and in Eμ-Myc primary cells cell line that 2DG could induce eIF2α phosphorylation, a typical ER stress marker (Fig.…”

Hyperactivation of 4E-Binding Protein 1 as a Mediator of Biguanide-Induced Cytotoxicity during Glucose Deprivation

“…Cells were cultured in either RPMI1640 (Wako Pure Chemical Industry; human fibrosarcoma HT1080 and stomach cancer MKN-74 cells) or Dulbecco's Modified Eagle's Medium (Wako Pure Chemical Industry; human cervical cancer HeLa and embryonic kidney 293T cells) supplemented with 10% FBS and 100 mg/mL of kanamycin and were cultured at 37 C in a humidified atmosphere of 5% CO 2 (20,21). Cell authentication was not done by the authors within the last 6 months.…”

“…It was recently reported that antidiabetic biguanides can exert antiproliferative and proapoptotic effects on different cancer types through AMPK-dependent and AMPK-independent mechanisms (19,20). These antidiabetic biguanides have also been shown to inhibit UPR activation and to induce selective cancer cell killing during glucose deprivation (21). Previous studies have focused on the actions of biguanides under normal growth conditions; however, it is largely unknown how biguanides affect cellular response to glucose deprivation, a representative tumor microenvironmental stress condition.…”

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

“…Hypoglycaemia is also known to activate the glucose-regulated protein 78 (GRP78), a molecular chaperone in the endoplasmic reticulum, which confers cytoprotective effects from apoptosis (Fu and Lee, 2006). Stress also activates the unfolded protein response system that ultimately activates survival proteins such as the heat shock protein Hsp90 (Saito et al, 2009). Additionally, prolonged hypoglycaemic stress has been known to contribute to oncogenic mutation (Yun et al, 2009) and activate survival pathways, including the PI3K/AKT pathway (Roberts et al, 2011).…”