Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma.

Within cells multiple related transcription factors targeting the same sequences may co-exist, leading to potential regulatory cooperativity, redundancy or competition. Yet the differential roles and biological functions of co-targeting transcription factors is poorly understood. In melanoma, three highly-related transcription factors are co-expressed: The mTORC1-regulated TFEB and TFE3, that are key effectors of a wide range of metabolic and microenvironmental cues; and MITF, that controls melanoma phenotypic identity.

Molecular Docking Studies of Ortho-Substituted Phenols to Tyrosinase Helps Discern If a Molecule Can Be an Enzyme Substrate.

Phenolic compounds with a position ortho to the free phenolic hydroxyl group occupied can be tyrosinase substrates. However, ortho-substituted compounds are usually described as inhibitors. The mechanism of action of tyrosinase on monophenols is complex, and if they are ortho-substituted, it is more complicated.

Considerations about the inhibition of monophenolase and diphenolase activities of tyrosinase. Characterization of the inhibitor concentration which generates 50 % of inhibition, type and inhibition constants. A review.

Tyrosinase is a copper oxidase enzyme which catalyzes the first two steps in the melanogenesis pathway, L-tyrosine to L-dopa conversion and, then, to o-dopaquinone and dopachrome. Hypopigmentation and, above all, hyperpigmentation issues can be originated depending on their activity. This enzyme also promotes the browning of fruits and vegetables.

Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy.

Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth. Here, we observed that some processes that allow the maintenance of basal autophagy in pancreatic cancer cells are controlled by protein methylation. Thus, by maintaining the methylation status of proteins such as PP2A and MRAS, these cells can sustain their autophagic activity.

Persister state-directed transitioning and vulnerability in melanoma.

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5B cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity.

The Relationship between the IC Values and the Apparent Inhibition Constant in the Study of Inhibitors of Tyrosinase Diphenolase Activity Helps Confirm the Mechanism of Inhibition.

Tyrosinase is the enzyme involved in melanization and is also responsible for the browning of fruits and vegetables. Control of its activity can be carried out using inhibitors, which is interesting in terms of quantitatively understanding the action of these regulators. In the study of the inhibition of the diphenolase activity of tyrosinase, it is intriguing to know the strength and type of inhibition.

MITF induces escape from innate immunity in melanoma.

Background: The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair.

Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions.

Hypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α.

PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation.

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation.

Rigid π-Extended Boron Difluoride Complex with Mega-Stokes Shift for Bioimaging.

The rational design of a rigid π-extended ligand, suitable for the formation of four-coordinate boron complexes, has led to the synthesis of the fused hexacyclic structure of carbazolo[2,1-]phenanthridine. The photophysical characterization of the novel fluorophore revealed a significant Stokes shift whose intramolecular charge transfer origin has been corroborated by computational calculations. The usefulness of the reported -difluoroboryl complex as fluorescent probe with large Stokes shift has been demonstrated for cancer cells imaging.

Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin.

Background: The resistance of melanoma cells to cisplatin restricts its clinical use. Therefore, the search for novel tumor inhibitors and effective combination treatments that sensitize tumor cells to this drug are still needed. We purified macrovipecetin, a novel heterodimeric C-type lectin, from Macrovipera lebetina snake venom and investigated its anti-tumoral effect on its own or combined with cisplatin, in human melanoma cells.

Structural and kinetic considerations on the catalysis of deoxyarbutin by tyrosinase.

Deoxyarbutin, a potent inhibitor of tyrosinase, could act as substrate of the enzyme. Oxytyrosinase is able to hydroxylate deoxyarbutin and finishes the catalytic cycle by oxidizing the formed o-diphenol to quinone, while the enzyme becomes deoxytyrosinase, which evolves to oxytyrosinase in the presence of oxygen. This compound is the only one described that does not release o-diphenol after the hydroxylation step.

Action of tyrosinase on alpha and beta-arbutin: A kinetic study.

The known derivatives from hydroquinone, α and β-arbutin, are used as depigmenting agents. In this work, we demonstrate that the oxy form of tyrosinase (oxytyrosinase) hydroxylates α and β-arbutin in ortho position of the phenolic hydroxyl group, giving rise to a complex formed by met-tyrosinase with the hydroxylated α or β-arbutin. This complex could evolve in two ways: by oxidizing the originated o-diphenol to o-quinone and deoxy-tyrosinase, or by delivering the o-diphenol and met-tyrosinase to the medium, which would produce the self-activation of the system.

Action of 2,2',4,4'-tetrahydroxybenzophenone in the biosynthesis pathway of melanin.

2,2',4,4'-tetrahydroxybenzophenone (Uvinul D50), a sunscreen used in cosmetics, has two effects in the melanin biosynthesis pathway. On the one hand, it acts a weak inhibitor of tyrosinase and on the other, it accelerates the conversion of dopachrome to melanin. Uvinul D50 was seen to behave as a weak competitive inhibitor: apparent constant inhibition=2.

Characterization of the action of tyrosinase on resorcinols.

The action of tyrosinase on resorcinol and some derivatives (4-ethylresorcinol, 2-methylresorcinol and 4-methylresorcinol) was investigated. If the catalytic cycle is completed with a reductant such as ascorbic acid or an o-diphenol such as 4-tert-butylcatechol, these compounds act as substrates of tyrosinase in all cases. The reaction can also be carried out, adding hydrogen peroxide to the medium.

Lebein, a Snake Venom Disintegrin, Induces Apoptosis in Human Melanoma Cells.

Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that are free of resistance mechanisms and side effects. Anti-neoplasic properties have been highlighted for different disintegrins from snake venom including Lebein; however, the exact effect of Lebein on melanoma has not yet been defined.

Tyrosinase-Catalyzed Hydroxylation of 4-Hexylresorcinol, an Antibrowning and Depigmenting Agent: A Kinetic Study.

4-Hexylresorcinol (HR) is a compound used in the food and cosmetic industries as an antibrowning and lightening agent. Its use is mainly attributed to its inhibitory effect on the enzyme tyrosinase. However, the enzyme hydroxylates HR to an o-diphenol, which it then oxidizes to an o-quinone, which rapidly isomerizes to p-quinone.

Unbalanced acetylcholinesterase activity in larynx squamous cell carcinoma.

Previous reports have demonstrated that a non-neuronal cholinergic system is expressed aberrantly in airways. A proliferative effect is exerted directly by cholinergic agonists through the activation of nicotinic and muscarinic receptors. In cancer, particularly those related with smoking, the mechanism through which tumour cells respond to aberrantly activated cholinergic signalling is a key question.

Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma.

Background: In airways, a proliferative effect is played directly by cholinergic agonists through nicotinic and muscarinic receptors activation. How tumors respond to aberrantly activated cholinergic signalling is a key question in smoking-related cancer. This research was addressed to explore a possible link of cholinergic signalling changes with cancer biology.