PSMB9 Codon 60 Polymorphisms Have No Impact on the Activity of the Immunoproteasome Catalytic Subunit B1i Expressed in Multiple Types of Solid Cancer

Abstract

The proteasome is a key regulator of cellular protein homeostasis and is a clinically validated anticancer target. The immunoproteasome, a subtype of proteasome expressed mainly in hematopoietic cells, was initially recognized for its role in antigen presentation during the immune response. Recently, the immunoproteasome has been implicated in several disease conditions including cancer and autoimmune disorders, but many of the factors contributing to these pathological processes remain unknown. In particular, the codon 60 polymorphism of the PSMB9 gene encoding the β1i immunoproteasome catalytic subunit has been investigated in the context of a variety of diseases. Despite this, previous studies have so far reported inconsistent findings regarding the impact of this polymorphism on proteasome activity. Thus, we set out to investigate the impact of the PSMB9 codon 60 polymorphism on the expression and activity of the β1i immunoproteasome subunit in a panel of human cancer cell lines. The β1i-selective fluorogenic substrate Acetyl-Pro-Ala-Leu-7-amino-4-methylcoumarin was used to specifically measure β1i catalytic activity. Our results indicate that the codon 60 Arg/His polymorphism does not significantly alter the expression and activity of β1i among the cell lines tested. Additionally, we also examined the expression of β1i in clinical samples from colon and pancreatic cancer patients. Our immunohistochemical analyses showed that ∼70% of clinical colon cancer samples and ∼53% of pancreatic cancer samples have detectable β1i expression. Taken together, our results indicate that the β1i subunit of the immunoproteasome is frequently expressed in colon and pancreatic cancers but that the codon 60 genetic variants of β1i display similar catalytic activities and are unlikely to contribute to the significant inter-cell-line and inter-individual variabilities in the immunoproteasome activity.

Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice

“…Furthermore the observed suppressive effects of LMP7 inhibition on the production of pro-inflammatory cytokines indicate a potential treatment option against inflammation-associated colon cancer. Previous reports established elevated expression of LMP2 and LMP7 in approximately 70% of human CRC tumor samples [ 24 , 25 ] which might facilitate direct targeting of malignant CRC cells by ONX 0914. Thus, ONX 0914 could potentially interfere with inflammation-driven CRC development during the preceding inflammation phase or directly with the growth of already established tumors.…”

Effects of an Anticarcinogenic Bowman-Birk Protease Inhibitor on Purified 20S Proteasome and MCF-7 Breast Cancer Cells

“…Despite both proteasome diversities, the expression and function of the immunoproteasome in different cancer types seem to be discrepant in the literature and still remain under investigation [47] . Regarding MCF-7 breast cancer cells, few descriptions of the expression and activity of the immunoproteasome subunits have been reported [48] – [50] . As shown, in MCF-7 cells both β5i/LMP7 and β1i/LMP2 subunits presented minimum expression levels when compared to other cancer cells, even with MCF-10A cells, indicating that immunoproteasomes are almost absent in MCF-7 breast tumor cells [48] .…”

Haplotypes of Polymorphic Antigen Processing Genes for Low Molecular Mass Polypeptides (LMP2 and LMP7) are Strongly Associated with Type 1 Diabetes in North India

“…While there was no difference in the mRNA expression of LMP2 in the R and H alleles, their chymotrypsin-like and trypsin-like activities were observed to be more in RR subjects compared to heterozygous RH subjects [22]. However, Park et al [23] did not find any effect of the codon 60 R/H polymorphism on either expression or catalytic activity of LMP2 in some cancer cell lines. Since the cancer cell lines themselves showed a lot of variability in protein expression of LMP2, it is possible that situation may be different in normal non-cancerous cells.…”