Endoplasmic reticulum protein ERp46 in prostate adenocarcinoma

Abstract

Abstract. Endoplasmic reticulum (ER) protein ERp46 is a member of the protein disulfide isomerase family of oxidoreductases, which facilitates the reduction of disulfides in proteins and their folding. Accumulation of misfolded proteins has been implicated in cancer. The objectives of the present study were to investigate the role of ERp46 in prostate cancer, its expression and its effects on prostate cancer growth. A tissue microarray with human prostate cancer and normal prostate tissue samples was stained for ERp46 followed by image analysis. Human prostate adenocarcinoma 22Rv1 cells were stably transfected with short hairpin RNA (shRNA) specific for ERp46, a non-effective scrambled control or a plasmid containing full-length human ERp46 cDNA, and cell growth was determined. Subcloned cells were treated with thapsigargin or tunicamycin to induce ER stress and lysates were subjected to western blot analysis for ER stress proteins. Subcutaneous xenografts of parental 22Rv1, ERp46-overexpressing (ERp46+), shERp46 or scrambled control cells were established in male inbred BALB/c nude mice (n=10/group). Tumor growth curves of the xenografts were constructed over a period of 30 days and subsequently the mice were sacrificed and the amount of serum prostate-specific antigen was determined. The results demonstrated increased ERp46 expression levels in prostate cancer tissue samples of Gleason ≥7 compared with normal prostate tissue samples. When ERp46 was stably knocked down using shRNA or overexpressed in prostate carcinoma 22Rv1 cells, tumor growth in vitro and in BALB/c nude mice was inhibited and accelerated, respectively. ERp46 overexpression led to reduced sensitivity to ER stress as indicated by higher half maximal inhibitory concentrations for tunicamycin and thapsigargin in ERp46+ cells. The shERp46 cells lost the ability to upregulate protein disulfide isomerase following tunicamycin-induced ER stress. The present study suggests a role for ERp46 as a therapeutic target in prostate cancer, given its expression profile in human prostate cancer, and its effect on prostate cancer cell growth.

Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer

“…In addition to PDI, Ero1α also oxidizes other PDI family members, such as ERp46 and P5 [49]. ERp46 promotes tumor growth in prostate carcinoma cells [50]; P5 promotes the proliferation of HeLa cells through activating the Wnt/β-catenin signaling pathway [51]. All these PDI homologues contain the a -type catalytic domains; thus, the strategy of disruption of Ero1α-PDI interaction might also be useful to inhibit cancer progression mediated by PDI homologues.…”

Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer

“…In the literature, varying culture conditions have been used, including different timepoints, inhibitor concentrations and serum levels. Several studies have used the inhibitors on prostate cancer cell lines, and we have used these studies to select our culture conditions for these experiments [ 39 , 40 , 41 , 42 , 43 , 44 ]. Following treatment with tunicamycin for 24 h, we detected levels of the ER stress marker GRP78 and EDEM3 using Western blotting.…”

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

“…On the other hand, the overexpression of TXNDC5 resulted in reduced sensitivity to ER stress when exposed to tunicamycin and thapsigargin. However, TXNDC5 knockout human prostate adenocarcinoma 22Rv1 cells lost the ability to upregulate protein disulfide isomerase after tunicamycin-induced ER stress [48]. Notably, during simvastatin-induced cell death through c-Jun N-terminal kinase (JNK) activation in DU145 human prostate cancer cells, TXNDC5 exhibited an opposite effect to vimentin, RAB1B, HMGCR, HNRNPK, NDRG1, and IDI1, as it was downregulated despite an increase in its molecular weight, suggesting significant post-translational modification [50].…”

“…Indeed, TXNDC5 is increased by ADT-induced hypoxia through HIF1A [42]. Duivenvoorden et al found that when TXNDC5 was stably knocked down using shRNA or overexpressed in prostate carcinoma 22Rv1 cells, tumor growth and proliferation in vitro and in BALB/c nude mice were inhibited and accelerated, respectively [47,48]. Additionally, the downregulation and upregulation of TXNDC5 in the corresponding xenografts showed several candidate genes, including NAAA, SH3BP4, and ID1, that were reciprocally up-and downregulated [49].…”