Abstract
The disulfide isomerase ERp57, originally found in the endoplasmic reticulum, is located in multiple cellular compartments, participates in diverse cell functions and interacts with a huge network of binding partners. It was recently suggested as an attractive new target for cancer therapy due to its critical role in tumor cell proliferation. Since a major bottleneck in cancer treatment is the occurrence of hypoxic areas in solid tumors, the role of ERp57 in cell growth was tested under oxygen depletion in the colorectal cancer cell line HCT116. We observed a severe growth inhibition when ERp57 was knocked down in hypoxia (1% O2) as a consequence of downregulated c-Myc, PLK1, PDPK1 (PDK1) and AKT (PKB). Further, irradiation experiments revealed also a radiosensitizing effect of ERp57 depletion under oxygen deprivation. Compared to ERp57, we do not favour PDPK1 as a suitable pharmaceutical target as its efficient knockdown/chemical inhibition did not show an inhibitory effect on proliferation.
Highlights
Despite advances in surgical quality, chemotherapies and irradiation, colorectal cancer (CRC) is still a predominant cancer in western countries due to marginal improvements in long-term survival rates[1,2]
To cover growth conditions that are found in solid tumors, we extended the experimental setup from normoxia (21% O2) to mild hypoxia (1% O2) and performed Annexin/ propodium iodide (Anx/PI) staining (Fig. 1A): Sole treatment of ERp57 KD or irradiation increased apoptosis albeit less pronounced than in normoxia
We further investigated a potential influence of ERp57 KD on hypoxia-inducible factor (HIF), the master regulator of O2 homeostasis
Summary
Despite advances in surgical quality, chemotherapies and irradiation, colorectal cancer (CRC) is still a predominant cancer in western countries due to marginal improvements in long-term survival rates[1,2]. In the ER, secretory proteins are synthesized, get folded and transported to their final destination in the cell membrane or outside the cell This whole process underlies a complex quality control and is prone to ER stress which can lead to cell death if the ER homeostasis is irreversibly disturbed. The thiol-oxidoreductase ERp57 (aka PDIA3, GRP58) was found as an ER-luminal protein that participates in the folding and quality control of glycoproteins, in particular in the assembly of the major histocompatibility complex class I7. It belongs to the family of protein disulfide isomerases (PDIs) and beside its role as a chaperone, it acts as a catalyst for disulfide bond formation in the rather oxidizing environment of the ER. We and others noticed a positive effect of ERp57 on mTOR-complex[1] phosphorylation s tatus[12], an overall picture of the interplay between ERp57 and growth-related pathways is still missing
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