Signaling Pathways in Melanogenesis D'Mello, Stacey A N; Finlay, Graeme J; Baguley, Bruce C ...
International Journal of Molecular Sciences,
07/2016, Letnik:
17, Številka:
7
Journal Article, Book Review
Recenzirano
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Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response ...to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.
The transcription factor SOX2 is essential for maintaining pluripotency in a variety of stem cells. It has important functions during embryonic development, is involved in cancer stem cell ...maintenance, and is often deregulated in cancer. The mechanism of SOX2 regulation has yet to be clarified, but the SOX2 gene lies in an intron of a long multi-exon non-coding RNA called SOX2 overlapping transcript (SOX2OT). Here, we show that the expression of SOX2 and SOX2OT is concordant in breast cancer, differentially expressed in estrogen receptor positive and negative breast cancer samples and that both are up-regulated in suspension culture conditions that favor growth of stem cell phenotypes. Importantly, ectopic expression of SOX2OT led to an almost 20-fold increase in SOX2 expression, together with a reduced proliferation and increased breast cancer cell anchorage-independent growth. We propose that SOX2OT plays a key role in the induction and/or maintenance of SOX2 expression in breast cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US ...National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme,
-2-(dimethylamino)-ethyl-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.
Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type of therapy are found to be resistant to several other drugs that are often ...quite different in both structure and mode of action, has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification of P-glycoprotein and other related transporters that were expressed in some cancer cells and could recognise and catalyse the efflux of diverse anticancer drugs from cells. A second advance came from an understanding of the mechanism of programmed cell death or apoptosis, leading to MDR mediated by increased to resistance to anticancer drug-induced apoptosis. A third advance came with the finding that the proliferation of human tumours was driven by a small population of self-renewing tumour cells, focussing attention on the MDR properties of these so-called tumour stem cells rather than on the cells that comprised the majority of the tumour population. A fourth advance was the delineation of features of the tumour microenvironment, including immunosuppression, which essentially provided tumour stem cells with an MDR phenotype. Most published work on the overcoming of MDR has concentrated on inhibition of drug transporters but the complexity of mechanisms contributing demands a broad strategy for the development of methods to overcome MDR in a clinical setting.
Disrupting tumour blood vessels Tozer, Gillian M; Kanthou, Chryso; Baguley, Bruce C
Nature reviews. Cancer,
200506, 2005-Jun, 2005-6-00, 20050601, Letnik:
5, Številka:
6
Journal Article
Recenzirano
Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in ...normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) - one of a structurally distinct group of drugs - is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Context.
Cosmological probes based on galaxy clusters rely on cluster number counts and large-scale structure information. X-ray cluster surveys are well suited for this purpose because they are far ...less affected by projection effects than optical surveys, and cluster properties can be predicted with good accuracy.
Aims.
The XMM Cluster Archive Super Survey, X-CLASS, is a serendipitous search of X-ray-detected galaxy clusters in 4176
XMM-Newton
archival observations until August 2015. All observations are clipped to exposure times of 10 and 20 ks to obtain uniformity, and they span ∼269 deg
2
across the high-Galactic latitude sky (|
b
| > 20°). The main goal of the survey is the compilation of a well-selected cluster sample suitable for cosmological analyses.
Methods.
We describe the detection algorithm, the visual inspection, the verification process, and the redshift validation of the cluster sample, as well as the cluster selection function computed by simulations. We also present the various metadata that are released with the catalogue, along with two different count-rate measurements, an automatic one provided by the pipeline, and a more detailed and accurate interactive measurement. Furthermore, we provide the redshifts of 124 clusters obtained with a dedicated multi-object spectroscopic follow-up programme.
Results.
With this publication, we release the new X-CLASS catalogue of 1646 well-selected X-ray-detected clusters over a wide sky area, along with their selection function. The sample spans a wide redshift range, from the local Universe up to
z
∼ 1.5, with 982 spectroscopically confirmed clusters, and over 70 clusters above
z
= 0.8. The redshift distribution peaks at
z
∼ 0.1, while if we remove the pointed observations it peaks at
z
∼ 0.3. Because of its homogeneous selection and thorough verification, the cluster sample can be used for cosmological analyses, but also as a test-bed for the upcoming eROSITA observations and other current and future large-area cluster surveys. It is the first time that such a catalogue is made available to the community via an interactive database which gives access to a wealth of supplementary information, images, and data.
NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an ...NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways.
This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional "knock-in" mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation.
Glutamine serves as an important nutrient with many cancer types displaying glutamine dependence. Following cellular uptake glutamine is converted to glutamate in a reaction catalysed by ...mitochondrial glutaminase. This glutamate has many uses, including acting as an anaplerotic substrate (via alpha-ketoglutarate) to replenish TCA cycle intermediates. CB-839 is a potent, selective, orally bioavailable inhibitor of glutaminase that has activity in Triple receptor-Negative Breast Cancer (TNBC) cell lines and evidence of efficacy in advanced TNBC patients.
A panel of eleven breast cancer cell lines was used to investigate the anti-proliferative effects of the glutaminase inhibitors CB-839 and BPTES in different types of culture medium, with or without additional pyruvate supplementation. The abundance of the TCA cycle intermediate fumarate was quantified as a measure if TCA cycle anaplerosis. Pyruvate secretion by TNBC cultures was then assessed with or without AZD3965, a monocarboxylate transporter 1 (MCT1) inhibitor. Finally, two dimensional (2D) monolayer and three dimensional (3D) spheroid assays were used to compare the effect of microenvironmental growth conditions on CB-839 activity.
The anti-proliferative activity of CB-839 in a panel of breast cancer cell lines was similar to published reports, but with a major caveat; growth inhibition by CB-839 was strongly attenuated in culture medium containing pyruvate. This pyruvate-dependent attenuation was also observed with a related glutaminase inhibitor, BPTES. Studies demonstrated that exogenous pyruvate acted as an anaplerotic substrate preventing the decrease of fumarate in CB-839-treated conditions. Furthermore, endogenously produced pyruvate secreted by TNBC cell lines was able to act in a paracrine manner to significantly decrease the sensitivity of recipient cells to glutaminase inhibition. Suppression of pyruvate secretion using the MCT1 inhibitor AZD3965, antagonised this paracrine effect and increased CB-839 activity. Finally, CB-839 activity was significantly compromised in 3D compared with 2D TNBC culture models, suggesting that 3D microenvironmental features impair glutaminase inhibitor responsiveness.
This study highlights the potential influence that both circulating and tumour-derived pyruvate can have on glutaminase inhibitor efficacy. Furthermore, it highlights the benefits of 3D spheroid cultures to model the features of the tumour microenvironment and improve the in vitro investigation of cancer metabolism-targeted therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In switched-mode power supplies - the predominant type of power converter in contemporary electronic equipment - ferrite magnetic components under dc bias conditions are typically large and have ...relatively high losses. The nature of these losses is not widely understood, and research in this area has been hampered by the difficulty of obtaining accurate core loss measurements. This paper reviews previous studies on the nature of core losses under dc bias, and presents new results, measured by a technique that has not previously been utilized for the measurement of core losses under dc bias conditions. The results show that ferrite core losses increase significantly with an increasing dc bias, and highlight the need for further research over a wider range of conditions to fully characterize the phenomenon.
The PI 3-kinase (PI3K) pathway has been implicated as a target for melanoma therapy.
Given the high degree of genetic heterogeneity in melanoma, we sought to understand the breadth of variation in ...PI3K signalling in the large NZM panel of early passage cell lines developed from metastatic melanomas.
We find the vast majority of lines show upregulation of this pathway, and this upregulation is achieved by a wide range of mechanisms. Expression of all class-IA PI3K isoforms was readily detected in these cell lines. A range of genetic changes in different components of the PI3K pathway was seen in different lines. Coding variants or amplification were identified in the PIK3CA gene, and amplification of the PK3CG gene was common. Deletions in the PIK3R1 and PIK3R2 regulatory subunits were also relatively common. Notably, no genetic variants were seen in the PIK3CD gene despite p110δ being expressed in many of the lines. Genetic variants were detected in a number of genes that encode phosphatases regulating the PI3K signalling, with reductions in copy number common in PTEN, INPP4B, INPP5J, PHLLP1 and PHLLP2 genes. While the pan-PI3K inhibitor ZSTK474 attenuated cell growth in all the lines tested, isoform-selective inhibition of p110α and p110δ inhibited cell growth in only a subset of the lines and the inhibition was only partial. This suggests that functional redundancy exists between PI3K isoforms. Furthermore, while ZSTK474 was initially effective in melanoma cells with induced resistance to vemurafenib, a subset of these cell lines concurrently developed partial resistance to PI3K inhibition. Importantly, mTOR-selective or mTOR/PI3K dual inhibitors effectively inhibited cell growth in all the lines, including those already resistant to BRAF inhibitors and ZSTK474.
Overall, this indicates a high degree of diversity in the way the PI3K pathway is activated in different melanoma cell lines and that mTOR is the most effective point for targeting the growth via the PI3K pathway across all of these cell lines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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