The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer

• Published in: Frontiers in medicine Vol. 10; p. 1209425
• Main Authors: Tychhon, Boranai, Allen, Jesse C, Gonzalez, Mayra A, Olivas, Idaly M, Solecki, Jonathan P, Keivan, Mehrshad, Velazquez, Vanessa V, McCall, Emily B, Tapia, Desiree N, Rubio, Andres J, Jordan, Connor, Elliott, David, Eiring, Anna M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12-07-2023
• Subjects: 19S proteasome; cancer; drug targets; Medicine; oncogenes; proteasome inhibition; drug targets; oncogenes; proteasome inhibition; 19S proteasome; cancer
• ISSN: 2296-858X; 2296-858X
• DOI: 10.3389/fmed.2023.1209425

The ubiquitin-proteasome system (UPS) is an intracellular organelle responsible for targeted protein degradation, which represents a standard therapeutic target for many different human malignancies. Bortezomib, a reversible inhibitor of chymotrypsin-like proteasome activity, was first approved by the FDA in 2003 to treat multiple myeloma and is now used to treat a number of different cancers, including relapsed mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success, bortezomib and other proteasome inhibitors are subject to severe side effects, and ultimately, drug resistance. We recently reported an oncogenic role for non-ATPase members of the 19S proteasome in chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and several different solid tumors. In the present study, we hypothesized that ATPase members of the 19S proteasome would also serve as biomarkers and putative therapeutic targets in AML and multiple other cancers.
We used data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) available at UALCAN and/or GEPIA2 to assess the expression and prognostic value of proteasome 26S subunit, ATPases 1-6 (PSMC1-6) of the 19S proteasome in cancer. UALCAN was also used to associate
-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of
genes across different cancer types.
The mRNA and protein expression of
-6 of the 19S proteasome were elevated in several cancers compared with normal controls, which often correlated with worse overall survival. In contrast, AML patients demonstrated reduced expression of these proteasome subunits compared with normal mononuclear cells. However, AML patients with high expression of
-5 had worse outcomes.
Altogether, our data suggest that components of the 19S proteasome could serve as prognostic biomarkers and novel therapeutic targets in AML and several other human malignancies.