P4HA1 knockdown in the breast cell line MDA231 Gln metabolism (part VI)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Cultured Cells
DISEASE(S): Cancer
PROVIDER: ST001139 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:The detachment of epithelial cells, but not cancer cells, causes anoikis due to reduced energy production. Invasive tumor cells generate three splice variants of the metastasis gene osteopontin. The cancer-specific form osteopontin-c supports anchorage-independence through inducing oxidoreductases and upregulating intermediates/enzymes in the hexose monophosphate shunt, glutathione cycle, glycolysis, glycerol phosphate shuttle, and mitochondrial respiratory chain. Osteopontin-c signaling upregulates glutathione (consistent with the induction of the enzyme GPX-4), glutamine and glutamate (which can feed into the tricarboxylic acid cycle). Consecutively, the cellular ATP levels are elevated. The elevated creatine may be synthesized from serine via glycine and also supports the energy metabolism by increasing the formation of ATP. Metabolic probing with N-acetyl-L-cysteine, L-glutamate, or glycerol identified differentially regulated pathway components, with mitochondrial activity being redox dependent and the creatine pathway depending on glutamine. The effects are consistent with a stimulation of the energy metabolism that supports anti-anoikis. Our findings imply a synergism in cancer cells between osteopontin-a, which increases the cellular glucose levels, and osteopontin-c, which utilizes this glucose to generate energy. mRNA profiles of MCF-7 cells transfected with osteopontin-a, osteopontin-c and vector control were generated by RNA-Seq, in triplicate, by Illumina HiSeq.
2014-02-21 | E-GEOD-55193 | biostudies-arrayexpress
Project description:IntroductionDetermining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary pteridines seen in certain cancers. Our companion study revealed that several folate-derived pteridines and lumazines correlated with tumorigenicity in an isogenic, progressive breast cancer cell model, providing direct evidence for the tumorigenic origin of pteridines.ObjectivesThis study sought to elucidate the pteridine biosynthetic pathway in a progressive breast cancer model via direct pteridine dosing to determine how pteridine metabolism changes with tumorigenicity.MethodsFirst, MCF10AT breast cancer cells were dosed individually with 15 pteridines to determine which pteridines were being metabolized and what metabolic products were being produced. Second, pteridines that were significantly metabolized were dosed individually across the progressive breast cancer cell model (MCF10A, MCF10AT, and MCF10ACA1a) to determine the relationship between each metabolic reaction and breast cancer tumorigenicity.ResultsSeveral pteridines were found to have altered metabolism in breast cancer cell lines, including pterin, isoxanthopterin, xanthopterin, sepiapterin, 6-biopterin, lumazine, and 7-hydroxylumazine (p < 0.05). In particular, isoxanthopterin and 6-biopterin concentrations were differentially expressed (p < 0.05) with respect to tumorigenicity following dosing with pterin and sepiapterin, respectively. Finally, the pteridine biosynthetic pathway in breast cancer cells was proposed based on these findings.ConclusionsThis study, along with its companion study, demonstrates that pteridine metabolism becomes disrupted in breast cancer tumor cells. This work highlights several key metabolic reactions within the pteridine biosynthetic pathway that may be targeted for further investigation and clinical applications.
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Project description:The telomeric amplicon at 8p12 is common in ER+ breast cancers. Array-CGH and expression analyses of 1172 tumors revealed ZNF703/Zeppo1 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor outcome. In the luminal MCF-7 cell line manipulation of ZNF703 expression altered transcription of genes also present within the primary tumor signature, including TGFBR2 (whose promoter was bound by ZNF703). Overexpression of ZNF703 rendered MCF-7 cells insensitive to TGFβ-induced suppression of mammosphere formation. Forced overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Together these data strongly point to ZNF703/Zeppo1 as a novel oncogene in Luminal B breast cancer. MCF-7 breast cancer cell line was infected with ZNF703 overexpression (ZNF703) or control (HIV) virus and following GFP sorting of infected cells, were transfected with control siRNA (siC) or siRNA against endogenous ZNF703 (siZNF), resulting in four different conditions: siC_HIV, siC_ZNF, siZNF_HIV and siZNF-ZNF. RNA for each condition was harvested from triplicate plates.
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Project description:Examination of effect of stable DDR1 knockdown by shRNA on transcriptional profile in BXPC3 cell line to understand role of DDR1 in tumorigenesis. Transcriptional profiles of parental BXPC3 cell line was compared to BXPC3 cells stably transfected with non-target shRNA or DDR1 shRNA, N=3 for each condition.
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Project description:Tumor proliferation, drug resistance and cell stemness are major difficulties that are encountered during breast cancer therapy and are often responsible for disease progression and cancer-related mortality. β-catenin is considered to be an invasion gene in breast cancer. However, how β-catenin regulates breast cancer cell proliferation and stemness remains unclear. In the present study, β-catenin knockdown by small interfering RNA in MDA-MB-468, a highly metastatic breast cancer cell line, inhibited the expression of β-catenin, Oct3/4 (stemness), survivin (anti-apoptosis) and BCRP (drug resistance). Knockdown of β-catenin enhanced the effects of fluorouracil (5-FU) chemotherapy on the proliferation of MDA-MB-468 cells. Thus, these preliminary results indicate that β-catenin knockdown enhanced 5-FU-induced proliferation inhibition in the breast cancer cell line MDA-MB-468, and indicate that combining 5-FU with gene silencing could be an advantageous option for enhancing the curative effect of chemotherapy in breast cancer and other malignancies.
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Project description:Metabolic reprogramming in tumor cells is considered one of the hallmarks of cancer. Many studies have been carried out in order to elucidate the effects of tumor cell metabolism on invasion and tumor progression. However, little is known about the immediate substrate preference in tumor cells. In this work, we wanted to study this short-time preference using the highly invasive, hormone independent breast cancer cell line MDA-MB-231. By means of Seahorse and uptake experiments, our results point to a preference for glucose. However, although both glucose and glutamine are required for tumor cell proliferation, MDA-MB-231 cells can survive two days in the absence of glucose, but not in the absence of glutamine. On the other hand, the presence of glucose increased palmitate uptake in this cell line, which accumulates in the cytosol instead of going to the plasma membrane. In order to exert this effect, glucose needs to be converted to glycerol-3 phosphate, leading to palmitate metabolism through lipid synthesis, most likely to the synthesis of triacylglycerides. The effect of glucose on the palmitate uptake was also found in other triple-negative, invasive breast cancer cell lines, but not in the non-invasive ones. The results presented in this work suggest an important and specific role of glucose in lipid biosynthesis in triple-negative breast cancer.
| S-EPMC7168317 | biostudies-literature
Project description:Cisplatin treatment confers the relative resistance to MCF-7 cells as compared to other breast cancer cell lines. One principal reason is that chemotherapeutic agents induce autophagy in these cells to inhibit apoptosis. Binding immunoglobulin protein (BiP), a master regulator of unfolded protein response (UPR) and 14-3-3ζ are two critical proteins upregulated in breast cancer rendering resistance to anticancer drugs. They also play pivotal roles in autophagy with crosstalk with the apoptotic pathways of UPR through certain regulators. Thus, BiP and 14-3-3ζ were selected as the candidate targets to enhance cell death and apoptosis. First, cisplatin resistance was induced and determined by MTT assay and qPCR in MCF-7 cells. Then, the apoptosis axis of UPR was activated by knocking down either BiP or 14-3-3ζ and overactivated by co-knockdown of BiP and 14-3-3ζ. Apoptosis assays were performed using flow cytometry, TUNEL assays utilized confocal microscopy followed by western blot analysis and caspase-3 and JNK activities were investigated to assess the outcomes. Finally, an autophagy assay followed by western blotting was performed to study the effects of co-knockdown genes on cell autophagy in the presence and absence of cisplatin. The present data indicated the enhancement of cisplatin sensitivity in MCF-7 cells co-knocked down in BiP and 14-3-3ζ compared with either gene knockdown. Upregulation of JNK and cleaved-PARP1 protein levels as well as caspase-3 and JNK overactivation confirmed the results. A marked attenuation of autophagy and Beclin1 as well as ATG5 downregulation were detected in co-knockdown cells compared to knockdown with either BiP or 14-3-3ζ. Cisplatin sensitization of MCF-7 cells through double-knockdown of BiP and 14-3-3ζ highlights the potential of targeting UPR and autophagy factors to increase the effect of chemotherapy.
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