Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

• Klíčová slova
• Warburg effect, anti-depressant, anti-inflammatory, anti-tumor, antioxidant, cancer, melatonin, metabolism, mitochondrial dysfunction, predictive preventive personalized medicine (PPPM/3PM),
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The tight regulation of cytoskeleton dynamics is required for a number of cellular processes, including migration, division and differentiation. YAP-TEAD respond to cell-cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of adult cell mechanical properties and function. Its regulation and role in pluripotent stem cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these cells are insensitive to contact inhibition. PSC inability to perceive cell-cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP-TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP-TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intracellular tension. We propose an aberrant activation of YAP-TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• angiomotiny metabolismus   MeSH
• buněčná diferenciace MeSH
• buněčné linie MeSH
• cytoskelet metabolismus   MeSH
• lidé MeSH
• lidské embryonální kmenové buňky metabolismus   MeSH
• mezoderm metabolismus   MeSH
• signální proteiny YAP genetika   metabolismus   MeSH
• signální transdukce MeSH
• transkripční faktory TEA domény genetika   metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• angiomotiny MeSH
• signální proteiny YAP MeSH
• TEAD1 protein, human MeSH Prohlížeč
• transkripční faktory TEA domény MeSH
• YAP1 protein, human MeSH Prohlížeč

The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• buněčné jádro účinky léků   MeSH
• cholangiokarcinom farmakoterapie   genetika   patologie   MeSH
• cytoplazma účinky léků   MeSH
• dasatinib aplikace a dávkování   MeSH
• fosfoproteiny genetika   MeSH
• fosforylace účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální proteiny YAP MeSH
• signální transdukce účinky léků   MeSH
• skupina kinas odvozených od src-genu antagonisté a inhibitory   genetika   MeSH
• transkripční faktory MeSH
• tyrosin genetika   MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty genetika   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• dasatinib MeSH
• fosfoproteiny MeSH
• LATS1 protein, human MeSH Prohlížeč
• LCK protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• signální proteiny YAP MeSH
• skupina kinas odvozených od src-genu MeSH
• transkripční faktory MeSH
• tyrosin MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty MeSH
• YAP1 protein, human MeSH Prohlížeč

Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described by a hierarchical model in which elements of Hippo pathway are under the control of focal adhesions (FAs). Here we unveil the molecular mechanism by which cell spreading and RhoA GTPase activity control FA formation through YAP to stabilize the anchorage of the actin cytoskeleton to the cell membrane. This mechanism requires YAP co-transcriptional function and involves the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity leads to the modification of cell mechanics, force development and adhesion strength, and determines cell shape, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify this Hippo effector as the key determinant of cell mechanics in response to ECM cues.

• MeSH
• buněčná diferenciace genetika   fyziologie   MeSH
• buněčná membrána metabolismus   MeSH
• buněčné linie MeSH
• buněčný převod mechanických signálů genetika   fyziologie   MeSH
• extracelulární matrix metabolismus   MeSH
• fokální adheze genetika   metabolismus   fyziologie   MeSH
• HEK293 buňky MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• mikrofilamenta metabolismus   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk genetika   fyziologie   MeSH
• proteiny buněčného cyklu MeSH
• rhoA protein vázající GTP genetika   metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktory genetika   metabolismus   MeSH
• tvar buňky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• proteiny buněčného cyklu MeSH
• rhoA protein vázající GTP MeSH
• transkripční faktory MeSH
• YY1AP1 protein, human MeSH Prohlížeč