Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression.

The transcription factor C/EBP-homologous protein (CHOP) is a key component of the terminal unfolded protein response (UPR) that mediates unresolvable endoplasmic reticulum stress-induced apoptosis. CHOP induction is known to cause cancer cell death. Chemicals that induce CHOP expression would thus be valuable as potential cancer therapeutics and as research tools. Here, we identified 5-nitrofuran-2-amide derivatives as small molecule activators of CHOP expression that induced apoptosis in triple negative breast cancer (TNBC) cells. Our preliminary structure-activity relationship studies indicated that compounds with an N-phenyl-5-nitrofuran-2-carboxamide skeleton were particularly potent inducers of TNBC cell apoptosis. The compounds activate CHOP expression via the PERK-eIF2α-ATF4 branch of the UPR. These results indicate that small molecule activators of CHOP expression may have therapeutic potential for TNBC.

Identification of small molecules that protect pancreatic ß cells against endoplasmic reticulum stress-induced cell death.

Endoplasmic reticulum (ER) stress plays an important role in the decline in pancreatic ß cell function and mass observed in type 2 diabetes. Here, we developed a novel ß cell-based high-throughput screening assay to identify small molecules that protect ß cells against ER stress-induced cell death. Mouse ßTC6 cells were treated with the ER stressor tunicamycin to induce ER stress, and cell death was measured as a reduction in cellular ATP. A collection of 17600 compounds was screened for molecules that promote ß cell survival. Of the approximately 80 positive hits, two selected compounds were able to increase the survival of human primary ß cells and rodent ß cell lines subjected to ER stressors including palmitate, a free fatty acid of pathological relevance to diabetes. These compounds also restored ER stress-impaired glucose-stimulated insulin secretion responses. We show that the compounds promote ß cell survival by reducing the expression of key genes of the unfolded protein response and apoptosis, thus alleviating ER stress. Identification of small molecules that prevent ER stress-induced ß cell dysfunction and death may provide a new modality for the treatment of diabetes.

Organization of the peripheral fly eye: the roles of Snail family transcription factors in peripheral retinal apoptosis.

The periphery of the fly eye contains a number of concentrically arranged cellular specializations that are induced by Wingless (Wg) signaling from the surrounding head capsule (HC). One of these is the pigment rim (PR), which is a thick layer of pigment cells that lies directly adjacent to the HC and completely circumscribes the rest of the retina. Many of the cells of the PR are derived from presumptive pigment cells that previously surrounded peripheral ommatidia that subsequently died. Here, we describe the Wg-elicited expression of Snail family transcription factors in the eye periphery that directs the ommatidial death and subsequent PR formation. These transcription factors are expressed only in a subset of the ommatidial cells not including the photoreceptors. Yet, the photoreceptors die and, thus, a non-autonomous death signal is released from the Snail-family-expressing cells that direct the death of the photoreceptors. In addition, Wg also elicits a similar peripheral expression of Notum, an enzyme that limits the extent of Wg signaling. Furthermore, we describe a later requirement for Snail family proteins in the 2 degrees and 3 degrees pigment cells throughout the main body of the eye.