Figure 5.

Resulting endoplasmic reticulum (ER) stress and unfolded protein response (UPR) gene network from a modelling approach using the set of differentially regulated genes common to all pancreatic cancer cell lines after nemorosone treatment. The genes showing strongest regulation (DDIT3, ATF3, CDKN1A, AREG, ASNS, VEGFA) were used as starting points for expanding the gene regulatory network in Ingenuity Pathway Analysis software using a knowledge-based algorithm applied to all 336 genes regulated by nemorosone treatment. The gene expression fold changes subsequent to the hypothetical nemorosone-induced calcium release from the ER are depicted. Red genes are up-regulated, green genes are down-regulated. Nemorosone-induced ER stress is sensed by three ER-resident proteins (PERK, ATF6, IRE1α), thus inducing downstream transcription factors ATF4, ATF3 and DDIT3 mainly involved in cell cycle regulation and apoptosis. If ER stress cannot be resolved through induction of pro-survival genes and growth factors, DDIT3 induced pro-apoptotic BCL2 family members like BAK1 and BCL2L11, thus initiating the caspase cascade. Expression levels of genes marked with # were inferred by quantitative PCR rather than microarray measurements (Figure 6C). GO, gene ontology.