PO-043 Targeting the thiol oxidoreductases ERp57 and PDI hits cancer cells on multiple fronts: proliferation, radioresistance and ER stress response (UPR)

Introduction Fast-growing tumour cells show enhanced protein synthesis and therefore depend on efficient folding for nascent export proteins in the endoplasmic reticulum (ER). Herein, the two most prominent ER resident thiol oxidoreductases ERp57 and PDI play important parts in formation of disulfide bonds in client proteins. This and the finding that both proteins fulfil various roles also in other compartments (i.e. cytoplasm, nucleus, cell membrane) encouraged us to investigate the impact of their depletion on colorectal cancer cells. Material and methods Using an inducible knockdown (KD) system we tested ERp57 and PDI deficiency in long term survival assays in normoxia and hypoxia combined with irradiation. Results and discussions KD of ERp57 or PDI triggered a severe attenuation of proliferation, but only ERp57 deficiency led to activation of the PERK-dependent UPR and apoptosis. When combined with an ERp57 KD, irradiation displayed the most dramatic growth reduction even under 1% oxygen. The absence of ERp57 reduced expression of cellular proliferation factors like c-Myc, PLK-1, AKT, PDPK1, ERK1,2 and others. Further, we demonstrated for the first time that PDI is an essential activator of the ER stress sensor PERK that enforces cancer cell survival under global ER stress in hypoxia. In the absense of ER stress, ERp57 functions as a reductase for PDI that keeps PERK in an inactive state. Conclusion Our data identified ERp57 and PDI as promising new targets for a mono- and combination anti-cancer therapy due to multiple cellular points of attack.