Expression data from human cancer cells treated with UPR modulators under ER stress conditions
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE13548 | GEO | 2009/05/20
SECONDARY ACCESSION(S): PRJNA110727
REPOSITORIES: GEO
Similar Datasets
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:Cancer cells consume large amounts of glucose because of their specific metabolic pathway. However, cancer cells exist in tumor tissue where glucose is insufficient. To survive, cancer cells likely have the mechanism to elude their glucose addiction. Here we show that functional mitochondria are essential if cancer cells are to avoid glucose addiction. Cancer cells with dysfunctional mitochondria, such as mitochondrial DNA-deficient rho0 cells and electron transport chain blocker-treated cells, were highly sensitive to glucose deprivation. Our data demonstrated that this sensitization was caused by failure of the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER). This study suggests a link between mitochondria and the ER during the UPR under glucose deprivation conditions and that mitochondria govern cell fate, not only through ATP production and apoptosis regulation but also through modulating the UPR for cell survival. Human cancer cell lines (HT-1080, HT-29, and mtDNA-deficient cells derived from these cell lines) were selected for RNA extraction and hybridization on Affymetrix microarrays. We examined the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER), of cancer cells under stress conditions. Abbreviations List: AA, antimycin A; Bu, buformin; Met, metformin; Phen, phenformin; Rot, rotenone; VST, versipelostatin; TM, tunicamycin; 2DG, 2-deoxyglucose; GS, glucose starvation. Capital S (_S) indicates the supernatant of sample including floating cells.
2010-05-28 | E-GEOD-16157 | biostudies-arrayexpress
Project description:Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. We found that compound C (also known as dorsomorphin) prevented the UPR and exerted enhanced cytotoxicity during glucose deprivation. The UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. To induce the UPR, we treated HT1080 cells for 18 hours under ER stress conditions by adding 10 mM 2-Deoxy-D-glucose (2DG) to culture medium. UPR inhibitors (compound C, versipelostatin and phenformin) were added just before 2DG was added in medium. Total 8 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays.
2012-10-11 | E-GEOD-32911 | biostudies-arrayexpress
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: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:The NGS-associated mRNA-seq analysis was conducted to survey transcriptome changes responding to three UPR inducers (tunicamycin, DTT, & Azetidine-2-cytosine) by four double mutant of three UPR-associated transcription factors (bZIP17, bZIP28, & bZIP60) and two activators (S1P & S2P).
2018-03-07 | GSE100371 | GEO
Project description:Spautin-1 as well as buformin showed preferential cytotoxicity under 2-deoxy-D-glucose (2DG)-stressed, but not tunicamycin-stressed conditions in HT-29 cells. By a microarray-based transcription analyses, we previously identified an unfolded protein response (UPR) expression signature, consisting of 246 probes up- or down-regulated in glucose starvation- and 2DG-stressed HT-29 and other cancer cell lines. Thus, we compared the effects of spautin-1 and buformin on the UPR transcriptional program. The two UPR inhibitors partly canceled 2DG-induced, but not TM-induced changes in UPR expression signature, indicating that spautin-1 can indeed suppress the UPR transcriptional program under 2DG-stressed conditions.
2022-07-07 | GSE189850 | GEO
Project description:ER protein homeostasis (proteostasis) is essential to facilitate proper folding and maturation of proteins in the secretory pathway. Loss of ER proteostasis can lead to the accumulation of misfolded or aberrant proteins in the ER and triggers the unfolded protein response (UPR). Here we find that the p97 adaptor UBXN1 is an important negative regulator of the UPR. Loss of UBXN1 sensitizes cells to ER stress and activates canonical UPR signaling pathways. This in turn leads to widespread upregulation of the ER stress transcriptional program. Using comparative, quantitative proteomics we show that deletion of UBXN1 results in a significant enrichment of proteins involved in ER-quality control processes including those involved in protein folding and import. Notably, we find that loss of UBXN1 does not perturb p97-dependent ER associated degradation. Our studies indicate that loss of UBXN1 increases translation in both resting and ER-stressed cells. Surprisingly, this process is independent of p97 function. Taken together, our studies have identified a new role for UBXN1 in repressing translation and maintaining ER proteostasis in a p97 independent manner.
2024-06-16 | PXD043686 | Pride