Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.

• Klíčová slova
• AMPK, CP: Cancer, CP: Metabolism, Cdk5, PRKAG2, SDHB, Warburg effect, cancer bioenergetics, neuroendocrine tumor, p53, pheochromocytoma, senescence,
• MeSH
• adenylátkinasa * metabolismus   MeSH
• cyklin-dependentní kinasa 5 metabolismus   MeSH
• energetický metabolismus MeSH
• fosforylace MeSH
• kinasa 3 glykogensynthasy metabolismus   MeSH
• myši MeSH
• neuroendokrinní karcinom * MeSH
• sukcináty MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• adenylátkinasa * MeSH
• cyklin-dependentní kinasa 5 MeSH
• kinasa 3 glykogensynthasy MeSH
• sukcináty MeSH

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivní transport - buněčné jádro * MeSH
• alfa-katenin metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• buňky A549 MeSH
• cytoplazma metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• kadheriny metabolismus   MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• myši nahé MeSH
• myši MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein dishevelled metabolismus   MeSH
• protein Wnt1 metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt metabolismus   MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• transkripční faktory MeSH
• transport proteinů MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• alfa-katenin MeSH
• DVL1 protein, human MeSH Prohlížeč
• fosfoproteiny MeSH
• kadheriny MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• nádorový supresorový protein p53 MeSH
• protein dishevelled MeSH
• protein Wnt1 MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasy aktivované AMP MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt MeSH
• signální proteiny YAP MeSH
• STK11 protein, human MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč
• transkripční faktory MeSH
• WNT1 protein, human MeSH Prohlížeč
• YAP1 protein, human MeSH Prohlížeč
• Yap1 protein, mouse MeSH Prohlížeč

Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.

• MeSH
• antitumorózní látky farmakologie   MeSH
• atriální natriuretický faktor metabolismus   MeSH
• časové faktory MeSH
• cytoprotekce účinky léků   MeSH
• dexamethason farmakologie   MeSH
• dieta MeSH
• fyziologický stres účinky léků   MeSH
• glukosa farmakologie   MeSH
• hyperglykemie patologie   MeSH
• kardiotoxiny toxicita   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• natriuretický peptid typu B metabolismus   MeSH
• omezení příjmu potravy metabolismus   MeSH
• protein 1 časné růstové odpovědi metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antitumorózní látky MeSH
• atriální natriuretický faktor MeSH
• dexamethason MeSH
• glukosa MeSH
• kardiotoxiny MeSH
• metformin MeSH
• natriuretický peptid typu B MeSH
• protein 1 časné růstové odpovědi MeSH
• proteinkinasy aktivované AMP MeSH
• proteinkinasy závislé na cyklickém AMP MeSH