Small extracellular vesicles modulated by αVβ3 integrin induce neuroendocrine differentiation in recipient cancer cells.

The ability of small extracellular vesicles (sEVs) to reprogram cancer cells is well established. However, the specific sEV components able to mediate aberrant effects in cancer cells have not been characterized. Integrins are major players in mediating sEV functions.

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells.

Unlabelled: Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling.

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias.

The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other's activity.

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML.

Data mining analysis of the PP2A cell cycle axis in mesothelioma patients.

Mesothelioma is an aggressive tumor that affects thousands of people every year. The therapeutic options for patients are limited; hence, a better understanding of mesothelioma biology is crucial to improve patient survival. To find new molecular targets and therapeutic strategies related to the protein phosphatase 2A (PP2A) network, we analyzed the gene expression of known PP2A inhibitors in mesothelioma patient samples.

A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity.

Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies.

Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import.

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC).

The Chromatin Assembly Factor Complex 1 (CAF1) and 5-Azacytidine (5-AzaC) Affect Cell Motility in Src-transformed Human Epithelial Cells.

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation.

Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.

Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner.

MYC-dependent recruitment of RUNX1 and GATA2 on the SET oncogene promoter enhances PP2A inactivation in acute myeloid leukemia.

The SET (I2PP2A) oncoprotein is a potent inhibitor of protein phosphatase 2A (PP2A) that regulates many cell processes and important signaling pathways. Despite the importance of SET overexpression and its prognostic impact in both hematologic and solid tumors, little is known about the mechanisms involved in its transcriptional regulation. In this report, we define the minimal promoter region of the gene, and identify a novel multi-protein transcription complex, composed of MYC, SP1, RUNX1 and GATA2, which activates expression in AML.

Protein Phosphatase 2A as a Therapeutic Target in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells in which several genetic and epigenetic aberrations have been described. Despite progressive advances in our understanding of the molecular biology of this disease, the outcome for most patients is poor. It is, therefore, necessary to develop more effective treatment strategies.

Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia.

Purpose: The SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A.

Experimental Design: In vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis, and clonogenic assays.

Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells.

Histone deacetylase inhibitors (HDACi) are a new class of anticancer agents that cause growth arrest, differentiation and/or apoptosis in many tumor cells. As acetylation regulates the activity of the anti-apoptotic transcription factor NF-kappaB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-kappaB activation and as a consequence potentiate HDACi-dependent apoptosis in breast cancer cells. We observed that the HDACi suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) induced cell death but also enhanced NF-kappaB-activity.