PSMC2

Last update 08 May 2025

Basic Info

Synonyms

26S proteasome AAA-ATPase subunit RPT1, 26S proteasome regulatory subunit 7, MSS1

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Introduction

Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.

100 Clinical Results associated with PSMC2

100 Translational Medicine associated with PSMC2

0 Patents (Medical) associated with PSMC2

160

Literatures (Medical) associated with PSMC2

01 Aug 2025·Cellular Signalling

PSMC2 upregulation enhances epithelial-to-mesenchymal transition in glioblastoma via activating AKT/GSK3β/β-catenin axis

Article

Author: Kola, Prithwish ; Deepak, K ; Borkar, Sachin A ; Roy, Pritam Kumar ; Mandal, Mahitosh ; Das, Chandan Kanta ; Sesodia, Rohit

Glioblastoma multiforme (GBM), a grade IV brain tumor, remains one of the most aggressive and difficult-to-treat cancers, emphasizing the urgent need for novel therapeutic targets. The dysregulation of the unfolded protein response, particularly involving the proteasomal pathway, contributes significantly to the pathogenesis of GBM. Proteasome 26S subunit ATPase 2 (PSMC2) has recently been identified as a potential factor in carcinogenesis; however, the molecular mechanisms involved remain unclear. In this study, we found significantly high expression of PSMC2 in GBM, with increased levels associated with an unfavorable prognosis. PSMC2 knockdown in GBM cell lines reduced proliferation, impaired migration, and induced apoptosis, while its overexpression enhanced epithelial-to-mesenchymal transition (EMT) related marker expression. Further, the tumorigenic effect of PSMC2 was confirmed in vivo as PSMC2 knockdown reduced the tumor volume and weight. Mechanistically, PSMC2 promoted malignancy via nuclear localizing of β-catenin by activating AKT/GSK3β/β-catenin axis, with AKT-mediated inhibitory phosphorylation of GSK3β enabling β-catenin activation. Besides, we used Lithium chloride to induce GSK3β phosphorylation which reversed the effects of PSMC2 knockdown, further validating this pathway. These findings demonstrate that PSMC2 drives GBM progression by regulating the AKT/GSK3β/β-catenin axis, positioning it as a promising biomarker and therapeutic target for GBM.

01 Mar 2025·Biochemical Pharmacology

PSMC2 promotes resistance against temozolomide in glioblastoma via suppressing JNK-mediated autophagic cell death

Article

Author: Jena, Bikash Chandra ; Mandal, Mahitosh ; Deepak, K ; Roy, Pritam Kumar ; Biswas, Angana ; Das, Abhijit ; Das, Chandan Kanta

Temozolomide is universally used to treat glioblastoma due to its unique ability to cross the blood-brain barrier and inhibit tumor growth through DNA alkylation. However, over time, the inevitable emergence of resistance to temozolomide impedes successful treatment of this cancer. As a result, there is an urgent need to identify new therapeutic targets to improve treatment outcomes for this malignancy. In this work, acquired temozolomide-resistant glioblastoma cell lines LN18 (LN18-TR) and T98G (T98G-TR) exhibited stronger aggressiveness and lower endoplasmic reticulum (ER) stress than their parental cells.. Besides, temozolomide resistance was associated with elevated proteasome activity that suppressed ER stress, which was restored upon inhibition of the proteasome with MG132. Specifically, our study revealed that the 19S proteasomal regulatory subunit PSMC2, which was overexpressed in adapted temozolomide-resistant glioblastoma cells, reduced pro-death autophagy and decreased temozolomide sensitivity in parental cells when overexpressed. While autophagy increased in parental cells following temozolomide treatment, it was not elevated in temozolomide-resistant glioblastoma cells. Genetic suppression of PSMC2 triggered the JNK signalling pathway causing phosphorylation of BCL2, allowing Beclin1 to be released from the BCL2-Beclin1 complex. This boosted autophagosome nucleation, increased pro-death autophagy, and restored apoptosis in temozolomide-resistant glioblastoma cells. Finally, targeting PSMC2 provided a unique method for interrupting autophagy-mediated ER stress maintenance and temozolomide resistance in glioblastoma.

01 Nov 2024·Molecular Neurobiology

A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells

Article

Author: Kumar, Ashok ; Dogra, Nilambra ; Singh, Parminder

Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15-18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes.

News (Medical) associated with PSMC2

18 Dec 2024

·www.globenewswire.com

Remedy Plan Therapeutics Initiates Dosing in Phase 1 Clinical Trial of RPT1G, a First-In-Class Hyperbolic NAMPT Inhibitor

Trial will evaluate the safety, pharmacokinetics and pharmacodynamics of RPT1G in adult healthy volunteers in anticipation of their upcoming oncology trial to treat patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS)GAITHERSBURG, Md., Dec. 18, 2024 (GLOBE NEWSWIRE) -- Remedy Plan Therapeutics, a privately-held clinical-stage pharmaceutical company transforming the field of NAMPT inhibition, announced today the initiation of an adult healthy volunteer Phase 1 clinical trial of its first-in-class, hyperbolic NAMPT inhibitor, RPT1G. As a hyperbolic NAMPT inhibitor, RPT1G is designed to target cells with high levels of NAMPT that occur in certain cancers, autoimmune and metabolic diseases, while avoiding on-target toxicity and thus preserving biological function in healthy cells. The Phase 1 randomized, double-blind, placebo-controlled clinical trial of RPT1G is being conducted in adult healthy volunteers in Australia (NCT06667765). The trial will evaluate RPT1G’s safety and pharmacokinetic properties while also exploring pharmacodynamic markers. Results from the Phase 1 clinical trial are expected in the first half of 2025 and will accelerate the company’s development of its oncology program in AML and high-risk MDS, currently planned to initiate in the second half of 2025. “We are thrilled to initiate our Phase 1 trial of RPT1G in healthy subjects. RPT1G is not only the first hyperbolic NAMPT inhibitor, but also the first NAMPT inhibitor to be tested in a healthy volunteer study, showcasing the importance of our preclinical work that clearly highlights the favorable safety profile of our hyperbolic NAMPT inhibitors,” stated Greg Crimmins, Ph.D., founder and CEO of Remedy Plan Therapeutics. “The results of this trial will enable us to initiate our subsequent trial in cancer patients at a starting dose that could provide meaningful therapeutic benefit.” About RPT1GRPT1G is a novel, small molecule NAMPT inhibitor that is designed to preserve biological function in healthy cells. The favorable efficacy and tolerability profile of RPT1G in preclinical models, compared to previously developed complete NAMPT inhibitors, provides robust support for its utility in treating hematological malignancies and solid tumors. In addition to single agent activity, preclinical studies have demonstrated that RPT1G strongly synergizes with current standard of care drugs and overcomes cancer cell resistance to venetoclax, and may offer improved treatment benefit for leukemia patients. Given the broad scientific validation of NAMPT upregulation in autoimmune and metabolic diseases, RPT1G analogues are also being evaluated as potential therapies for those diseases. About Remedy Plan TherapeuticsRemedy Plan Therapeutics is a privately-held, clinical-stage pharmaceutical company transforming the field of NAMPT inhibition. Remedy Plan’s lead asset, RPT1G, is the first hyperbolic NAMPT inhibitor to be tested in humans and has potential for broad therapeutic applications in cancer, autoimmune and metabolic diseases. Remedy Plan initiated a Phase 1 clinical trial of RPT1G in adult healthy subjects in November 2024. To learn more about Remedy Plan, please visit https://remedyplan.com/. Investor Relations and Media Contact:Parisa Moghaddam-Taaheripress@remedyplan.com

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