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

Boranai Tychhon; Jesse C Allen; Mayra A Gonzalez; Idaly M Olivas; Jonathan P Solecki; Mehrshad Keivan; Vanessa V Velazquez; Emily B McCall; Desiree N Tapia; Andres J Rubio; Connor Jordan; David Elliott; Anna M Eiring

doi:10.3389/fmed.2023.1209425

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

Front Med (Lausanne). 2023 Jul 12:10:1209425. doi: 10.3389/fmed.2023.1209425. eCollection 2023.

Authors

Affiliations

¹ Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, United States.
² Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, United States.
³ L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, United States.

Abstract

Introduction: 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.

Methods: 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 PSMC1-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of PSMC genes across different cancer types.

Results: The mRNA and protein expression of PSMC1-6 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 PSMC2-5 had worse outcomes.

Discussion: 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.

Keywords: 19S proteasome; cancer; drug targets; oncogenes; proteasome inhibition.