Transcriptome analysis of doxorubicin-treated MCF7 breat cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE244574 | GEO | 2024/03/27
REPOSITORIES: GEO
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Project description:Summary: Cancer imparts an increased risk for venous thromboembolism (VTE). Direct mechanisms linking VTE with malignancy remain unknown. Our characterization of Doxorubicin (DOX)-resistant MCF7 breast cancer cells revealed links with antithrombotic pathways, as an anticoagulant transcriptional profile was observed. Specifically, the intracellular anticoagulant Tissue Factor Pathway Inhibitor 1 (TFPI1) protein was elevated and functional in all resistant models tested; TFPI1 accumulation coincided with reduced thrombin. TFPI1 overexpression in unselected cells elevated pro-malignant gene markers and increased DOX resistance. Furthermore, TFPI1 and Breast Cancer Resistant Protein (BCRP) levels increased early and remained sustained during selection. Finally, consistent with antithrombin-mediated hypoxic metastasis, Hypoxia-Inducible Factor 1 alpha (HIF1alpha) was elevated in drug resistant and TFPI1 overexpressing cells. Thus, increased TFPI1 may create an intratumoral hypoxic environment, potentially leading to drug resistance. MCF7 cells were selected for DOX resistance by first treating the cells with 1 microM DOX for 48 hours. The cells were then exposed to 100 nM DOX for 2 weeks. After this period, the surviving cells were resistant to further DOX treatment.
2013-06-01 | E-MTAB-1643 | biostudies-arrayexpress
Project description:MTC-DOX is Doxorubicin or DOX, a chemotherapy drug, that is adsorbed, or made to "stick", to magnetic beads (MTCs). MTCs are tiny, microscopic particles of iron and carbon. When DOX is added to MTCs, DOX attaches to the carbon part of the MTCs. MTC-DOX is directed to and deposited in the area of a tumor, where it is thought that it then "leaks" through the blood vessel walls. Once in the surrounding tissues, it is thought that Doxorubicin becomes "free from" the magnetic beads and will then be able to act against the tumor cells. The iron component of the particle has magnetic properties, making it possible to direct MTC-DOX to specific tumor sites in the liver by placing a magnet on the body surface. It is hoped that MTC-DOX used with the magnet may target the chemotherapy drug directly to liver tumors and provide a treatment to patients with cancers that have spread to the liver.
| 2007949 | ecrin-mdr-crc
Project description:doxorubicin is commonly used for hematological malignancies. Since some of PTCL patients resistance to dox and die due to refractory disease or relapse, enhanced knowledge about drug response mechanisms is required to improve treatment outcome. we found an increased expression of HDAC3 in T lymphoma H9 cells following dox exprosure, we compared the gene expression profiles of H9 cells pre/post treated with doxorubicin to explore the potential mechanism of the high expression of HDAC3
2024-04-18 | GSE260756 | GEO
Project description:Breast cancer remains one of the leading causes of death in women, being the chemotherapeutic agent doxorubicin (Dox) among the most widely standard chemotherapy options for its treatment. However, its effective use has been severely limited owing to its well-documented cardiotoxic side effect that can lead to heart failure in a subset of patients. We have previously shown that a specific population of mesenchymal stem cells (MSCs) present immunomodulatory and regenerative properties, mainly granted by its secretome (CM), whose potential was improved when produced under 3D conditions. In cancer, the role of MSCs is still contradictory, with literature reporting both cancer promoting and suppressive effects. Therefore, we aimed at determining the effect of concomitant exposure of Dox with CM from 3D (CM3D) and 2D (CM2D) MSC cultures in breast cancer cells (MDA-MB-231) and in non-tumour breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes. As such, the whole secretome was obtained by collecting and concentrating the culture media conditioned by MSCs in 2D (CM2D) and 3D (CM3D). A Ge-LC-MS/MS proteomic analysis revealed that CM3D effects may be linked to MSC cytoprotection and tumour development, namely through regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP-8, PDCD5), invasion (TIMP-1/2), oxidative stress (AIFM1, CD9, GSR) and inflammation (ANXA5, CDH13, GDF-15). Overall, MSC-derived CM3D decreased Dox-induced cytotoxic effects on non-tumour breast cells and cardiomyocytes, without compromising Dox chemotherapeutic nature, highlighting the potential use of CM3D as an adjuvant in chemotherapy to reduce off-target side effects.
2023-03-11 | PXD025633 | Pride
Project description:The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy of standard chemotherapy by reducing their dosage and side effects. The standard chemotherapeutic drug for breast and other cancer types- doxorubicin(DOX), also known as Adriamycin (an anthracycline) has several disadvantages including severe side effects and development of drug resistance. Recently, we reported the broad spectrum pharmacological activity and potential markers of Australian propolis extract (AP-1). In the present study, we explored the synergistic interactions of AP-1 with DOX against MCF-7 cells by implementing different synergy quantitation models. To identify the potential anticancer metabolites in AP-1, biochemometric and metabolomics-driven study was performed. Furthermore, we evaluated the molecular mechanisms involved by analysing the apoptotic profile (using flow cytometry and proteome array of 35 apoptotic proteins) and oxidative status (using reactive oxygen species detection) of the MCF-7 cells upon treatment with the most synergistic combination. The underlying synergistic mechanism against the MCF-7 cells was also studied using label-free quantification proteomics analysis. Five prenylated stilbenes were identified as the most discriminant metabolites in the most active AP-1 fraction, three of them previously isolated from AP-1 with IC50 values in the range 0.68-2.7 µM against the MCF-7 cells. Strong synergy was observed when AP-1 was combined with DOX in the ratio of 100:0.29 (w/w) as validated by different synergy quantitation models including combination index (CI), HSA, ZIP, LOEWE, and BLISS. AP-1 significantly enhanced the inhibitory effect of DOX (p < 0.05) against the MCF-7 cell proliferation in a dose-dependent manner with significant reduction of ROS production (p < 0.05; compared to DOX alone). AP-1 also enhanced the apoptotic effect of DOX significantly after 24 h of treatment with a shift of DOX-induced necrosis to apoptosis. Significant upregulation of catalase, HTRA2/Omi, FADD together with TRAIL-mediated apoptosis, DR5 and DR4 (p < 0.05) was observed which contributed to the anti-proliferative activity of AP-1 against the MCF-7 cells. The enhancement of pro-apoptotic p27, PON2 and catalase with reduction of anti-apoptotic XIAP, HSP60 and HIF-1α may be associated with the improved apoptosis in the MCF-7 cells observed in the Annexin V-7AAD flow cytometry analysis of the synergistic combination compared to the mono treatments. Furthermore, a significant increase of antioxidant proteins including catalase and PON2 was observed upon treatment with the synergistic combination which may be associated with the parallel enhancement of apoptosis. Shotgun proteomics in the synergistic combination-treated cells identified 21 significantly dysregulated proteins involving the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and curtailed RIF1 encoded proteins. The overexpression of UPF2 was noticed after the treatment with the synergistic combination which could assist to overcome doxorubicin resistance-associated long non-coding RNA and decline the metastasis of the MCF-7 cells. In summary, we propose a promising AP-1 and DOX synergistic combination against the MCF-7 cells and highlighted the possible synergistic mechanisms of action together with the key prenylated metabolites of AP-1. Further in vivo and clinical studies are warranted on this synergistic combination.
2021-07-26 | PXD026331 | Pride
Project description:Glucose shortage can lead to ROS accumulation and thus induce mitochondrial damage in breast cancer (BC) cells. However, the role of mitophagy in cancer cells under glucose starvation remains unclear. Here, we showed that mesencephalic astrocyte-derived neurotrophic factor (MANF)-mediated mitophagy facilitates BC cell survival under glucose starvation. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, under glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF’s nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to parkin RBR E3 ubiquitin protein ligase (PRKN), a key mitophagy regulator, in the mitochondria. Under glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF–PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results provide a mechanistic explanation for the prosurvival role of MANF-mediated mitophagy in BC cells under glucose starvation and may point to targetable vulnerabilities.
2023-11-06 | PXD046689 | iProX
Project description:Breast cancer remains one of the leading causes of death in women, being the chemotherapeutic agent doxorubicin (Dox) among the most widely standard chemotherapy options for its treatment. However, its effective use has been severely limited owing to its well-documented cardiotoxic side effect that can lead to heart failure in a subset of patients. We have previously shown that a specific population of mesenchymal stem cells (MSCs) present immunomodulatory and regenerative properties, mainly granted by its secretome (CM), whose potential was improved when produced under 3D conditions. In cancer, the role of MSCs is still contradictory, with literature reporting both cancer promoting and suppressive effects. Therefore, we aimed at determining the effect of concomitant exposure of Dox with CM from 3D (CM3D) and 2D (CM2D) MSC cultures in breast cancer cells (MDA-MB-231) and in non-tumour breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes. As such, the whole secretome was obtained by collecting and concentrating the culture media conditioned by MSCs in 2D (CM2D) and 3D (CM3D). A Ge-LC-MS/MS proteomic analysis revealed that CM3D effects may be linked to MSC cytoprotection and tumour development, namely through regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP-8, PDCD5), invasion (TIMP-1/2), oxidative stress (AIFM1, CD9, GSR) and inflammation (ANXA5, CDH13, GDF-15). Overall, MSC-derived CM3D decreased Dox-induced cytotoxic effects on non-tumour breast cells and cardiomyocytes, without compromising Dox chemotherapeutic nature, highlighting the potential use of CM3D as an adjuvant in chemotherapy to reduce off-target side effects.
2022-02-17 | PXD029795 | Pride
Project description:Genetic profile of immune cells was characterised in primary breast tumours upon treatment with Anakinra, Dox+Zol, Anakinra+Dox+Zol
2021-07-28 | GSE174638 | GEO
Project description:Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A's role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.
2022-06-08 | GSE205550 | GEO
Project description:Although the development of tyrosine kinase inhibitors (TKIs), including BCR-ABL1 targeted therapies, rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast crisis (BC) progression remains a critical challenge. Here, we elucidate the significance of FLT3 signaling in the acquisition of drug resistance in BC-CML. Mechanistically, FLT3 expression in CML cells activated FLT3-JAK-STAT3-TAZ-TEAD-CD36 pathway, which conferred resistance to wide range of tyrosine kinase inhibitors (TKIs). Remarkably, a subgroup of BC-CML patients who expressed FLT3 showed strong correlation with the prognostic factors of CML independent of recurrent BCR-ABL1 mutations. We demonstrate that combining FLT3 inhibitors with BCR-ABL1 targeted therapies or single treatment with ponatinib can overcome drug resistance and promote cell death in patient-derived FLT3+ BC-CML cells and mouse xenograft models. Our findings reveal the mechanism of FLT3-mediated drug resistance in BC progression and suggest the inclusion of FLT3 as a therapeutic target for this defined group of patients.
2023-11-15 | GSE226360 | GEO