Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

• Klíčová slova
• AMPK, AR, CREB, LKB1, Metformin, Prostate Cancer, STAT3, mTORC1,
• MeSH
• diabetes mellitus 2. typu * MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• metformin * farmakologie   MeSH
• mTORC1 metabolismus   MeSH
• myši MeSH
• nádory prostaty * genetika   patologie   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví 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
• metformin * MeSH
• mTORC1 MeSH
• proteinkinasy aktivované AMP MeSH
• STAT3 protein, human MeSH Prohlížeč
• Stat3 protein, mouse MeSH Prohlížeč
• Stk11 protein, mouse MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

• Klíčová slova
• DHAP, GPD2, cancer, ether lipids, mitochondria,
• MeSH
• energetický metabolismus MeSH
• ethery metabolismus   MeSH
• glycerolfosfátdehydrogenasa * genetika   metabolismus   MeSH
• lidé MeSH
• mitochondrie * enzymologie   MeSH
• myši MeSH
• nádory * enzymologie   patologie   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ethery MeSH
• glycerolfosfátdehydrogenasa * MeSH
• protoonkogenní proteiny c-akt * MeSH

BACKGROUND: Hexokinases (HKs) are well-studied enzymes catalyzing the first step of glycolysis. However, non-canonical regulatory roles of HKs are still incompletely understood. Here, we hypothesized that HKs comprise one of the missing links between high-dose metformin and the inhibition of the respiratory chain in cancer. METHODS: We tested the isoenzyme-specific regulatory roles of HKs in ovarian cancer cells by examining the effects of the deletions of HK1 and HK2 in TOV-112D ovarian adenocarcinoma cells. We reverted these effects by re-introducing wild-type HK1 and HK2, and we compared the HK1 revertant with the knock-in of catalytically dead HK1 p.D656A. We subjected these cells to a battery of metabolic and proliferation assays and targeted GC×GC-MS metabolomics. RESULTS: We found that the HK1 depletion (but not the HK2 depletion) sensitized ovarian cancer cells to high-dose metformin during glucose starvation. We confirmed that this newly uncovered role of HK1 is glycolysis-independent by the introduction of the catalytically dead HK1. The expression of catalytically dead HK1 stimulated similar changes in levels of TCA intermediates, aspartate and cysteine, and in glutamate as were induced by the HK2 deletion. In contrast, HK1 deletion increased the levels of branched amino acids; this effect was completely eliminated by the expression of catalytically dead HK1. Furthermore, HK1 revertants but not HK2 revertants caused a strong increase of NADPH/NADP ratios independently on the presence of glucose or metformin. The HK1 deletion (but not HK2 deletion) suppressed the growth of xenotransplanted ovarian cancer cells and nearly abolished the tumor growth when the mice were fed the glucose-free diet. CONCLUSIONS: We provided the evidence that HK1 is involved in the so far unknown glycolysis-independent HK1-metformin axis and influences metabolism even in glucose-free conditions.

• Klíčová slova
• Aerobic glycolysis, Hexokinase, Metabolism reprogramming, Metformin, Nicotinamide adenine dinucleotide phosphate, Oxidative phosphorylation,
• Publikační typ
• časopisecké články MeSH

Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-alpha (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

• Klíčová slova
• mTORC1, Hif1a, clonal expansion, developmental biology, glycolysis, hypoxia-induced factor 1-alpha, mechanistic target of rapamycin complex 1, mitotic division limit, mouse, retinal progenitor cell,
• MeSH
• ependymální buňky patologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• hamartin genetika   metabolismus   MeSH
• kmenové buňky patologie   MeSH
• mitóza MeSH
• mTORC1 genetika   metabolismus   MeSH
• myši MeSH
• retina patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• hamartin MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• mTORC1 MeSH
• Tsc1 protein, mouse MeSH Prohlížeč

Metformin is currently the most prescribed drug for treatment of type 2 diabetes mellitus in humans. It has been well established that long-term treatment with metformin improves glucose tolerance in mice by inhibiting hepatic gluconeogenesis. Interestingly, a single dose of orally administered metformin acutely lowers blood glucose levels, however, little is known about the mechanism involved in this effect. Glucose tolerance, as assessed by the glucose tolerance test, was improved in response to prior oral metformin administration when compared to vehicle-treated mice, irrespective of whether the animals were fed either the standard or high-fat diet. Blood glucose-lowering effects of acutely administered metformin were also observed in mice lacking functional AMP-activated protein kinase, and were independent of glucagon-like-peptide-1 or N-methyl-D-aspartate receptors signaling. [18F]-FDG/PET revealed a slower intestinal transit of labeled glucose after metformin as compared to vehicle administration. Finally, metformin in a dose-dependent but indirect manner decreased glucose transport from the intestinal lumen into the blood, which was observed ex vivo as well as in vivo. Our results support the view that the inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin.

• MeSH
• biologický transport účinky léků   MeSH
• diabetes mellitus 2. typu farmakoterapie   metabolismus   MeSH
• glukosa metabolismus   MeSH
• glukózový toleranční test MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• krevní glukóza metabolismus   MeSH
• lidé MeSH
• metformin farmakologie   terapeutické užití   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• střevní sliznice účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glukosa MeSH
• hypoglykemika MeSH
• krevní glukóza MeSH
• metformin MeSH
• proteinkinasy aktivované AMP MeSH

UNLABELLED: To examine the association between premorbid metformin exposure and mortality, hyperlactatemia, and organ dysfunction in sepsis. DATA SOURCES: PubMed and EMBASE (with Medline via Ovid) databases were searched for all studies of premorbid metformin exposure and sepsis published between January 1974 and August 2018. STUDY SELECTION: Studies of at least 20 patients with sepsis that reported data on metformin use, mortality, and/or organ dysfunction were independently selected. DATA EXTRACTION: Two reviewers abstracted data on study design, settings, study quality, participants, metformin exposure, mortality, initial lactate levels, and organ dysfunction. Risk of bias was independently assessed. DATA SYNTHESIS: Eight observational studies fulfilled our criteria, comprising 4,144 patients with sepsis including 562 diabetics on metformin. Premorbid metformin exposure was associated with reduced mortality in sepsis (odds ratio, 0.57; 95% CI, 0.40-0.80). Between studies heterogeneity was low (i 2 = 43%; τ2 = 0.1; p = 0.09). Premorbid metformin exposure was not significantly associated with initial lactate levels (mean difference, 0.39 [-0.50 to 1.28]; i 2 = 72%; p = 0.39). CONCLUSIONS: The meta-analysis suggests that premorbid metformin exposure is associated with decreased mortality in sepsis but not with hyperlactatemia. What are the potential mechanisms and whether there is any effect on organ dysfunction remain unclear.

• Klíčová slova
• metformin, metformin-associated lactic acidosis, mortality, organ dysfunction, sepsis, systematic review,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

• MeSH
• biguanidy farmakologie   MeSH
• fenformin farmakologie   MeSH
• glycerolfosfátdehydrogenasa metabolismus   MeSH
• hnědá tuková tkáň cytologie   MeSH
• hypoglykemika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina jantarová metabolismus   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• metformin farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• peroxid vodíku farmakologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biguanidy MeSH
• fenformin MeSH
• glycerolfosfátdehydrogenasa MeSH
• hypoglykemika MeSH
• kyselina jantarová MeSH
• metformin MeSH
• peroxid vodíku MeSH
• reaktivní formy kyslíku MeSH