Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis.

Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers.

Isoprenylcysteine carboxyl methyltransferase (ICMT) promotes invadopodia formation and metastasis in cancer cells.

Isoprenyl cysteine carboxyl methyltransferase (ICMT) catalyzes the last step of the prenylation pathway. Previously, we found that high ICMT levels enhance tumorigenesis in vivo and that its expression is repressed by the p53 tumor suppressor. Based on evidence suggesting that some ICMT substrates affect invasive traits, we wondered if this enzyme may promote metastasis.

The p53 tumor suppressor regulates AKR1B1 expression, a metastasis-promoting gene in breast cancer.

Alteration of metabolism in cancer cells is a central aspect of the mechanisms that sustain aggressive traits. Aldo-keto reductase 1 B1 (AKR1B1) catalyzes the reduction of several aldehydes to alcohols consuming NADPH. Nevertheless, the ability of AKR1B1 to reduce different substrates renders difficult to comprehensively ascertain its biological role.

Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity.

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker.

PHGDH expression increases with progression of Alzheimer's disease pathology and symptoms.

Chen et al. reveal an increase of phosphoglycerate dehydrogenase (PHGDH) mRNA and protein levels in two mouse models and four human cohorts in Alzheimer's disease brains compared to age- and sex-matched control brains. The increase of PHGDH expression in human brain correlates with symptomatic development and disease pathology.

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher.

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53.

Missense mutations in the gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway.

Design, synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents.

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53.

Expression of zebrafish cpsf6 in embryogenesis and role of protein domains on subcellular localization.

CPSF6 is a component of the CFIm complex, involved in mRNA 3'end processing. Despite increasing interest on this protein as a consequence of proposed roles in cancer and HIV infection, several aspects of CPSF6 biological function are poorly understood. In this work we studied the expression of the zebrafish ortholog cpsf6 in early stages of embryo development.

Author Correction: Specific Phospholipids Regulate the Acquisition of Neuronal and Astroglial Identities in Post-Mitotic Cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Identification of a CIP4 PKA phosphorylation site involved in the regulation of cancer cell invasiveness and metastasis.

CDC42 interacting protein 4 (CIP4) is a CDC42 effector that coordinates membrane deformation and actin polymerization. The correlation of CIP4 overexpression with metastatic capacity has been characterized in several types of cancer. However, little information exists on how CIP4 function is regulated.

Isoprenylcysteine carboxy methyltransferase (ICMT) is associated with tumor aggressiveness and its expression is controlled by the p53 tumor suppressor.

Isoprenyl cysteine carboxyl methyltransferase (ICMT) plays a key role in post-translational regulation of prenylated proteins. On the basis of previous results, we hypothesized that the p53 pathway and ICMT expression may be linked in cancer cells. Here, we studied whether WT p53 and cancer-associated p53 point mutants regulate ICMT levels and whether ICMT overexpression affects tumor progression.

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through retro-aza-Michael//aza-Michael Isomerizations.

The design and synthesis of biomass-derived triazoles and the in vitro evaluation as potential anticancer agents are described. The discovery of base-catalyzed retro-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues.

Specific Phospholipids Regulate the Acquisition of Neuronal and Astroglial Identities in Post-Mitotic Cells.

Hitherto, the known mechanisms underpinning cell-fate specification act on neural progenitors, affecting their commitment to generate neuron or glial cells. Here, we show that particular phospholipids supplemented in the culture media modify the commitment of post-mitotic neural cells in vitro. Phosphatidylcholine (PtdCho)-enriched media enhances neuronal differentiation at the expense of astroglial and unspecified cells.

Akap350 Recruits Eb1 to The Spindle Poles, Ensuring Proper Spindle Orientation and Lumen Formation in 3d Epithelial Cell Cultures.

The organization of epithelial cells to form hollow organs with a single lumen requires the accurate three-dimensional arrangement of cell divisions. Mitotic spindle orientation is defined by signaling pathways that provide molecular links between specific spots at the cell cortex and astral microtubules, which have not been fully elucidated. AKAP350 is a centrosomal/Golgi scaffold protein, implicated in the regulation of microtubule dynamics.

Dynamic regulation of Pin1 expression and function during zebrafish development.

The prolyl isomerase Pin1 plays a key role in the modulation of proline-directed phosphorylation signaling by inducing local conformational changes in phosphorylated protein substrates. Extensive studies showed different roles for Pin1 in physiological processes and pathological conditions such as cancer and neurodegenerative diseases. However, there are still several unanswered questions regarding its biological role.

Cooperation of p53 mutations with other oncogenic alterations in cancer.

Following the initial findings suggesting a pro-oncogenic role for p53 point mutants, more than 30 years of research have unveiled the critical role exerted by these mutants in human cancer. A growing body of evidence, including mouse models and clinical data, has clearly demonstrated a connection between mutant p53 and the development of aggressive and metastatic tumors. Even if the molecular mechanisms underlying mutant p53 activities are still the object of intense scrutiny, it seems evident that full activation of its oncogenic role requires the functional interaction with other oncogenic alterations.

Disarming mutant p53 oncogenic function.

In the last decade intensive research has confirmed the long standing hypothesis that some p53 point mutants acquire novel activities able to cooperate with oncogenic mechanisms. Particular attention has attracted the ability of several such mutants to actively promote the development of aggressive and metastatic tumors in vivo. This knowledge opens a new dimension on rational therapy design, suggesting novel strategies based on pharmacological manipulation of those neomorphic activities.

Wiring the oncogenic circuitry: Pin1 unleashes mutant p53.

Unlike several tumor suppressor genes, whose inactivation is due to deletions or truncating mutations, TP53 is most frequently hit by missense mutations in its DNA binding domain.

A Pin1/mutant p53 axis promotes aggressiveness in breast cancer.

TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation.

Parkinson disease-associated DJ-1 is required for the expression of the glial cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells.

Mutations in PARK7/DJ-1 are associated with autosomal recessive, early onset Parkinson disease (PD). DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. Here we show that DJ-1 plays an essential role in the expression of rearranged during transfection (RET), a receptor for the glial cell line-derived neurotrophic factor, a neuroprotective molecule for dopaminergic neurons, the main target of degeneration in PD.