Reductive death is averted by a conserved de novo lipogenic switch
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE277946 | GEO | 2026/05/25
REPOSITORIES: GEO
Similar Datasets
Project description:To study the overabundance of reducing equivalents, termed reductive stress, specifically for NADH reductive stress, we introduce a soluble transhydrogenase from E. coli (EcSTH) as a novel genetically encoded tool to promote NADH overproduction
2023-09-01 | GSE232115 | GEO
Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide phenformin was used as antidiabetic drug due to its antihyperglycaemic effect, but was withdrawn from the market in the 1970s for safety reasons. In recent years, biguanides received great interest in oncology research after an epidemiological study showed a link between the treatment with metformin, another biguanide with a better safety profile, and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.
2018-12-17 | GSE122608 | GEO
Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide phenformin was used as antidiabetic drug due to its antihyperglycaemic effect, but was withdrawn from the market in the 1970s for safety reasons. In recent years, biguanides received great interest in oncology research after an epidemiological study showed a link between the treatment with metformin, another biguanide with a better safety profile, and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.
2018-12-17 | GSE122606 | GEO
Project description:The unfolded protein response (UPR) is a cellular defense mechanism against glucose deprivation, a cell condition that occurs in solid tumors. A key feature of the UPR is the activation of the transcription program that allows the cell to cope with endoplasmic reticulum (ER) stress. We used micoarrays to show that the UPR transcription program is disrupted by the antitumor macrocyclic compound versipelostatin (VST) and antidiabetic biguanides metformin, buformin and phenformin, depending on cellular glucose availability. Experiment Overall Design: Total 42 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays. Experiment Overall Design: To induce the UPR, we treated cells (HeLa, HT-29, HT1080, MKN74) for 15 or 18 hours under ER stress conditions by replacing the medium with glucose-free medium or by adding either 2-Deoxy-D-glucose (2DG) or Tunicamycin (TM) to glucose-containing medium. UPR modulators (VST, biguanides or pyrvinium pamoate) were added at various final concentrations immediately after cells were placed in glucose-free medium or just before the chemical stressors were added to glucose-containing culture medium.
2009-06-01 | E-GEOD-13548 | biostudies-arrayexpress
Project description:The unfolded protein response (UPR) is a cellular defense mechanism against glucose deprivation, a cell condition that occurs in solid tumors. A key feature of the UPR is the activation of the transcription program that allows the cell to cope with endoplasmic reticulum (ER) stress. We used micoarrays to show that the UPR transcription program is disrupted by the antitumor macrocyclic compound versipelostatin (VST) and antidiabetic biguanides metformin, buformin and phenformin, depending on cellular glucose availability. Keywords: stress response, drug response
2009-05-20 | GSE13548 | GEO
Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide metformin is a widely used antidiabetic drug, which has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, another biguanide withdrawn from the marked as antidiabetic due to safety reasons, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.
2018-12-17 | GSE122605 | GEO
Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide metformin is a widely used antidiabetic drug, which has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, another biguanide withdrawn from the marked as antidiabetic due to safety reasons, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.
2018-12-17 | GSE122604 | GEO
Project description:Reduced cancer incidence has been reported among type II diabetics treated with metformin. Metformin exhibits anti-proliferative and anti-neoplastic effects associated with inhibition of mTORC1, but the mechanisms are poorly understood. We provide the first genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) and metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's anti-proliferative activity can be explained by selective translational suppression of mRNAs encoding cell cycle regulators via the mTORC1/4E-BP pathway. Thus, metformin selectively inhibits mRNA translation of encoded proteins that promote neoplastic proliferation, motivating further studies of this compound and related biguanides in cancer prevention and treatment. MCF7 cells were treated with rapamycin, metformin or PP242 at concentrations that inhibited proliferation to 50% of control. Both cytoplasmic and polysome-associated mRNA was extracted from treatments and a vehicle treated control and probed with microarrays.
2012-05-20 | E-GEOD-36847 | biostudies-arrayexpress
Project description:NADPH has been long well-recognized as a key cofactor for antioxidant defense and reductive biosynthesis. Here we report a metabolism-independent function of NADPH in modulating epigenetic status and transcription. We found that reduction of cellular NADPH levels by silencing malic enzyme (ME) or G6PD impairs global histone acetylation and transcription in both adipocytes and tumor cells. These effects can be reversed by supplementation of exogenous NADPH or inhibition of histone deacetylase 3 (HDAC3). Mechanistically, NADPH or inhibition of histone deacetylase 3 (HDAC3). Mechanistically,NADPH directly interacts with HDAC3 and interrupts the association between HDAC3 and its co-activator Ncor2 (SMRT) or Ncor1, thereby impairs HDAC3 activation. Interestingly, it appears that NADPH and Ins(1,4,5,6)P4 bind to the same domains on HDAC3, and NADPH has relatively higher affinity towards HDAC3. Thus, while Ins(1,4,5,6)P4 acts as an ‘intermolecular glue’, NADPH may function as a HDAC3-Ncor assembly inhibitor. Collectively, our findings uncovered a previous unidentified and metabolism-independent role of NADPH in controlling epigenetic change and gene expression by acting as an endogenous inhibitor of HDAC3.
2020-11-27 | GSE137694 | GEO
Project description:Metformin is a therapeutically versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying many of its clinical effects, including attenuated postprandial glucose excursions, elevated intestinal glucose uptake, and increased production of lactate, Lac-Phe and GDF15, remain unclear. Here, we map these and other clinical effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving uptake of excess glucose and converting it to lactate and Lac-Phe. Notably, the glucose-lowering effect of another biguanide, phenformin, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
2025-12-04 | GSE293164 | GEO