Abstract
Ever since the ubiquitin proteasome system was characterized, efforts have been made to manipulate its function to abrogate the progression of cancer. As a result, the anti-cancer drugs bortezomib, carfilzomib, and ixazomib targeting the 26S proteasome were developed to treat multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, among others. Despite success, adverse side effects and drug resistance are prominent, raising the need for alternative therapeutic options. We recently demonstrated that knockdown of the 19S regulatory components, 26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3), resulted in increased apoptosis of chronic myeloid leukemia (CML) cells, but had no effect on normal controls, suggesting they may be good targets for therapy. Therefore, we hypothesized that PSMD1 and PSMD3 are potential targets for anti-cancer therapeutics and that their relevance stretches beyond CML to other types of cancers. In the present study, we analyzed PSMD1 and PSMD3 mRNA and protein expression in cancerous tissue versus normal controls using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), comparing expression with overall survival. Altogether, our data suggest that PSMD1 and PSMD3 may be novel putative targets for cancer prognosis and therapy that are worthy of future investigation.
Highlights
The ubiquitin proteasome system (UPS) is a highly regulated, multi-enzyme complex that allows cells and tissues to maintain protein homeostasis [1]
The diseases analyzed in UALCAN included bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), pheochromocytoma and paraganglioma (PCPG), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), thyroid carcinoma (THCA), thymoma (THYM), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC)
We recently demonstrated that knockdown of PSMD1 and PSMD3 resulted in increased apoptosis of chronic myeloid leukemia (CML) cells but not normal cord blood controls, implicating they may be good targets for therapy [31]
Summary
The ubiquitin proteasome system (UPS) is a highly regulated, multi-enzyme complex that allows cells and tissues to maintain protein homeostasis [1]. Depending on the demands of the cell, the protein turnover rate fluctuates in part through activity of this biological system [2,3] In diseases such as cancer, the UPS can go rampant due to the extreme requirements of malignant cells. BTZ has found its success as a reversible inhibitor by binding to the β5 subunit of the 20S core complex to inhibit its chymotrypsin-like enzymatic activity. This inhibition causes an accumulation of ubiquitylated proteins and subsequent caspase-mediated apoptosis of myeloma cells [6].
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