Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.

Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ Receptor Ligands with Antiproliferative Properties.

A series of novel σ receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents.

EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer.

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g.

Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer.

Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH.

Novel σ antagonists designed for tumor therapy: Structure - activity relationships of aminoethyl substituted cyclohexanes.

Depending on the substitution pattern and stereochemistry, 1,3-dioxanes 1 with an aminoethyl moiety in 4-position represent potent σ receptor antagonists. In order to increase the stability, a cyclohexane ring first replaced the acetalic 1, 3-dioxane ring of 1. A large set of aminoethyl substituted cyclohexane derivatives was prepared in a six-step synthesis.

Pharmacodynamic and Pharmacokinetic Properties of Full Phosphorothioate Small Interfering RNAs for Gene Silencing .

State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency.

Mitochondrial fission promotes self-renewal and tumorigenic potential in prostate cancer.

The emergence of therapy-resistant cancer stem cells (CSCs) limit the efficacy of prostate cancer treatment. Using genetic knockdown and chemical inhibitors, we demonstrate the critical role of Bromodomain Containing 4 (BRD4) in promoting mitochondrial fission and sustaining CSC expansion. These findings provide a new paradigm for developing novel treatment strategies for prostate cancer.

Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer.

Background: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients.

Transcriptional Reprogramming and Inhibition of Tumor-propagating Stem-like Cells by EC-8042 in ERG-positive Prostate Cancer.

Background: The TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and SP1 may be instrumental in sustaining the tumorigenic and metastatic phenotype and could represent a potential vulnerability in ERG fusion-positive tumors.

Objective: To test the activity of EC-8042, a compound able to block SP1, in cellular and mouse models of ERG-positive prostate cancer.

Transcriptional Reprogramming and Novel Therapeutic Approaches for Targeting Prostate Cancer Stem Cells.

Prostate cancer is the most common malignancy in men and the second cause of cancer-related deaths in western countries. Despite the progress in the treatment of localized prostate cancer, there is still lack of effective therapies for the advanced forms of the disease. Most patients with advanced prostate cancer become resistant to androgen deprivation therapy (ADT), which remains the main therapeutic option in this setting, and progress to lethal metastatic castration-resistant prostate cancer (mCRPC).

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies.

Publisher Correction: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.

In the HTML version of this article initially published, the name of author Diletta Di Mitri was miscoded in the XML such that Di was included as part of the given name instead of the family name. The error has been corrected in the HTML version of the article.

Overview of Genetically Engineered Mouse Models of Prostate Cancer and Their Applications in Drug Discovery.

Prostate cancer (PCa) is the most common malignant visceral neoplasm in males in Western countries. Despite progress made in the early treatment of localized malignancies, there remains a need for therapies effective against advanced forms of the disease. Genetically engineered mouse (GEM) models are valuable tools for addressing this issue, particularly in defining the cellular and molecular mechanisms responsible for tumor initiation and progression.

Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.

The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus.

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood.

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter.

Targeting Promoter-Associated Noncoding RNA In Vivo.

There are many classes of noncoding RNAs (ncRNAs), with wide-ranging functionalities (e.g., RNA editing, mediation of mRNA splicing, ribosomal function).

MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression.

Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells.

A Small-Molecule Inhibitor of Lin28.

New discoveries in RNA biology underscore a need for chemical tools to clarify their roles in pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an RNA binding protein (RBP) Lin28, which docks onto a conserved sequence in let-7 precursor RNA molecules and prevents their maturation. Thus, the Lin28/let-7 interaction might be an attractive drug target, if not for the well-known difficulty in targeting RNA-protein interactions with drugs.

The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment.

Metastatic prostate cancer represents a yet unsolved clinical problem due to the high frequency of relapse and treatment resistance. Understanding the pathways that lead to prostate cancer progression is an important task to prevent this deadly disease. The ETS transcription factor ESE3/EHF has an important role in differentiation of human prostate epithelial cells.