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Biochemical Pharmacology Jun 2024Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA...
Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.
PubMed: 38944395
DOI: 10.1016/j.bcp.2024.116398 -
Cellular Signalling Jun 2024The 26S proteasome non-ATPase regulatory subunit 11 is a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins, and PSMD11 plays a key...
The 26S proteasome non-ATPase regulatory subunit 11 is a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins, and PSMD11 plays a key role in the regulation of embryonic stem cell proteasome activity. However, the role of PSMD11 in hepatocellular carcinoma has not been studied. In this study, it was found that the expression of PSMD11 in HCC tissues was significantly higher than that in para-cancerous tissues, and was associated with poor prognosis. The results of in vitro experiments showed that PSMD11 knockdown could effectively inhibit the proliferation and apoptosis of hepatoma cell lines, and flow cytometry showed that the G0/G1 phase was significantly prolonged. Through protein spectrometry, immunoprecipitation and in vitro experiments, it was found that PSMD11 can promote the proliferation of hepatocellular carcinoma through regulating the ubiquitination of CDK4 and enhancing its protein stability. This study explores the mechanism of action of PSMD11 in hepatocellular carcinoma and provides new insights for the treatment of hepatocellular carcinoma.
PubMed: 38944255
DOI: 10.1016/j.cellsig.2024.111279 -
Scientific Reports Jun 2024Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into...
Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into non-invasive ductal or lobular carcinoma (DCIS) and invasive carcinoma (ILC or IDC) underscores its heterogeneity. The ubiquitin-proteasome system plays a crucial role in breast cancer, with inhibitors targeting the 26S proteasome showing promise in clinical treatment. The Cullin-RING ubiquitin ligases, including CUL3, have direct links to breast cancer. This study focuses on CUL3 as a potential biomarker, leveraging high-throughput sequencing, gene expression profiling, experimental and data analysis tools. Through comprehensive analysis using databases like GEPIA2 and UALCAN, as well as TCGA datasets, CUL3's expression and its association with prognostic values were assessed. Additionally, the impact of CUL3 overexpression was explored in MCF-7 and MDA-MB-231 breast cancer cell lines, revealing distinct differences in molecular and phenotypic characteristics. We further profiled its expression and localization in breast cancer tissues identifying prominent differences between luminal A and TNBC tumors. Conclusively, CUL3 was found to be associated with cell cycle progression, and DNA damage response, exhibiting diverse roles depending on the tumor's molecular type. It exhibits a tendency to act as an oncogene in triple-negative tumors and as a tumor suppressor in luminal A types, suggesting a potential significance in breast cancer progression and therapeutic directions.
Topics: Humans; Cullin Proteins; Female; Prognosis; Breast Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Gene Expression Profiling; MCF-7 Cells; Triple Negative Breast Neoplasms
PubMed: 38942922
DOI: 10.1038/s41598-024-65692-z -
Cell Death & Disease Jun 2024Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity...
Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.
Topics: Humans; Receptor, ErbB-2; Adenocarcinoma of Lung; Lung Neoplasms; Neoplastic Stem Cells; Neoplasm Proteins; Phenotype; Animals; Mice; Cell Line, Tumor; Ubiquitin-Protein Ligases
PubMed: 38942760
DOI: 10.1038/s41419-024-06853-w -
Moving the needle on proteasome inhibitor-induced pulmonary arterial hypertension: a definite maybe.The European Respiratory Journal Jun 2024
Topics: Humans; Proteasome Inhibitors; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Bortezomib
PubMed: 38942441
DOI: 10.1183/13993003.00946-2024 -
Cancer Cell Jun 2024KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity,...
KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.
PubMed: 38942026
DOI: 10.1016/j.ccell.2024.06.001 -
Biochemistry Jun 2024Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein...
Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein clearance. Here, we investigated the formation particulars of intracellular protein AGEs and sought to elucidate the molecular events implicated in the impact of cellular clearance systems. The formation and accumulation of intracellular protein AGEs increased protein aggregation and protease resistance, potentially overwhelming the ubiquitin-proteasome system (UPS). At high levels of protein AGEs, the abundance of many E3 ligases decreased and the overall ubiquitination level was reduced, all of which indicated decreased UPS activity. On the other hand, autophagy activity was stimulated, as evidenced by the upregulation of autophagy marker LC3II and important proteins in autophagosome and autolysosome formation, as well as downregulation of mTOR. Understanding the functional impacts of intracellular protein AGEs on the UPS and autophagy could pave the way for the future development of pharmaceutical agents targeting AGE-related diseases.
PubMed: 38941592
DOI: 10.1021/acs.biochem.4c00250 -
MBio Jun 2024Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an...
UNLABELLED
Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an essential viral DNA replication protein, maintains viral persistence by interacting with host Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complexes, which subsequently induces LT's proteasomal degradation, restricting MCPyV DNA replication. SCF E3 ubiquitin ligases require their substrates to be phosphorylated to bind them, utilizing phosphorylated serine residues as docking sites. The MCPyV LT unique region (MUR) is highly phosphorylated and plays a role in multiple host protein interactions, including SCF E3 ubiquitin ligases. Therefore, this domain highly governs LT stability. Though much work has been conducted to identify host factors that restrict MCPyV LT protein expression, the kinase(s) that cooperates with the SCF E3 ligase remains unknown. Here, we demonstrate that casein kinase 1 alpha (CK1α) negatively regulates MCPyV LT stability and LT-mediated replication by modulating interactions with the SCF β-TrCP. Specifically, we show that numerous CK1 isoforms (α, δ, ε) localize in close proximity to MCPyV LT through proximity ligation assays (PLA) and CK1α overexpression mainly resulted in decreased MCPyV LT protein expression. Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication. The expression level of the gene transcripts is higher in MCPyV-positive MCC, suggesting a vital role of CK1α in limiting MCPyV replication required for establishing persistent infection.
IMPORTANCE
Merkel cell polyomavirus (MCPyV) large tumor antigen is a polyphosphoprotein and the phosphorylation event is required to modulate various functions of LT, including viral replication. Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.
PubMed: 38940554
DOI: 10.1128/mbio.01117-24 -
Advanced Science (Weinheim,... Jun 2024Retention of metabolic end-products in the bodily fluids of patients with chronic kidney disease (CKD) may lead to uremia. The uremic toxin indoxyl sulfate (IS), a...
Retention of metabolic end-products in the bodily fluids of patients with chronic kidney disease (CKD) may lead to uremia. The uremic toxin indoxyl sulfate (IS), a tryptophan metabolite, is an endogenous ligand of aryl hydrocarbon receptor (AhR). It is clarified that the upregulation and activation of AhR by IS in tubular epithelial cells (TECs) promote renal senescence and fibrosis. Renal TEC-specific knockout of AhR attenuates renal senescence and fibrosis, as well as the suppression of PGC1α-mediated mitochondrial biogenesis in ischemia reperfusion (IR)- or IS-treated CKD mice kidneys. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) attenuates IS-induced cell senescence and extracellular matrix production in cultured TECs. Mechanistically, AhR is able to interact with PGC1α and promotes the ubiquitin degradation of PGC1α via its E3 ubiquitin ligase activity. In summary, the elevation and activation of AhR by the accumulated uremic toxins in the progression of CKD accelerate renal senescence and fibrosis by suppressing mitochondrial biogenesis via promoting ubiquitination and proteasomal degradation of PGC1α.
PubMed: 38940381
DOI: 10.1002/advs.202402066 -
International Journal of Molecular... Aug 2024The ubiquitin (Ub)‑proteasome system (UPS) plays a pivotal role in maintaining protein homeostasis and function to modulate various cellular processes including... (Review)
Review
The ubiquitin (Ub)‑proteasome system (UPS) plays a pivotal role in maintaining protein homeostasis and function to modulate various cellular processes including skeletal cell differentiation and bone homeostasis. The Ub ligase E3 promotes the transfer of Ub to the target protein, especially transcription factors, to regulate the proliferation, differentiation and survival of bone cells, as well as bone formation. In turn, the deubiquitinating enzyme removes Ub from modified substrate proteins to orchestrate bone remodeling. As a result of abnormal regulation of ubiquitination, bone cell differentiation exhibits disorder and then bone homeostasis is affected, consequently leading to osteoporosis. The present review discussed the role and mechanism of UPS in bone remodeling. However, the specific mechanism of UPS in the process of bone remodeling is still not fully understood and further research is required. The study of the mechanism of action of UPS can provide new ideas and methods for the prevention and treatment of osteoporosis. In addition, the most commonly used osteoporosis drugs that target ubiquitination processes in the clinic are discussed in the current review.
Topics: Humans; Osteoporosis; Ubiquitination; Animals; Ubiquitin; Proteasome Endopeptidase Complex; Bone Remodeling; Ubiquitin-Protein Ligases
PubMed: 38940355
DOI: 10.3892/ijmm.2024.5392