Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA310695 | ENA |
REPOSITORIES: ENA
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Project description:Chemotherapy resistance presents a major hurdle for cancer treatment. We proposed to identify the molecular changes through which breast cancer cells evolve resistance to conventional treatment, here cisplatin, so targeted therapy can be developed. Candidate approach RNAi screening was combined with cisplatin treatment in order to identify molecular pathways conferring survival advantages. The screening identified ATP7A, a copper transport ATPase responsible for the intercellular movement and sequestering of cisplatin, as a therapeutic target. Copper chelation with tetrathiomolybdate (TM) targets ATP7A. TM in combination with cisplatin sensitized drug-resistant breast cancer cells. Allograft and xenograft models in aythymic mice treated with TM/cisplatin combination therapy inhibited tumor growth and increased survival compared with monotreated mice. Examination of the molecular effects of TM on cisplatin efficacy in drug-resistant tumors revealed reduced levels of APT7A, reduced cisplatin sequestering by ATP7A and increased nuclear availability of cisplatin. Further, we showed that TM treatment combined with cisplatin reduced the half-life of ATP7A in human breast cancer cell lines. This finding offered the potential to combat drug platinum-resistant tumors and sensitize patients to conventional breast cancer treatments by identifying and targeting resistant tumors’ unique molecular adaptations.
2017-06-19 | GSE77515 | GEO
Project description:Although three proteasome inhibitors have been used for liquid tumor treatment, their effectiveness against solid tumors remains inadequate. To address this issue, we employed a drug combination strategy and discovered that ammonium tetrathiomolybdate (TM) and AMD3100 can sensitize solid cancer cell lines to proteasome inhibitors. Mechanistically, we found that TM and AMD3100 reduce proteasome activity by decreasing the protein level of PSMB5. This reduction occurs through the activation of the AMPK pathway, which inhibits STAT3 phosphorylation. Notably, our in vivo studies revealed that drug combinations retarded tumor growth dependent on CD8+ T cells. The combination of bortezomib with TM or AMD3100 induced cancer cell antigen presentation and the production of CCL5, which together stimulated the recruitment and generation of cytotoxic CD8+ T cells. This study identifies new synergistic lethal pairs that enhance the effectiveness of bortezomib-centered therapy against breast cancer.
2025-05-01 | GSE296112 | GEO
Project description:Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and marked sensitivity to TM. Global proteomic and metabolomic profiling identified TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We identified the AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricted copper deficiency to mitochondria and phenocopied TM-mediated alterations. These findings identify a novel copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
2021-10-26 | PXD027089 | Pride
Project description:Copper-related cell death, cuproptosis, involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins. Here, glioblastoma (GBM) stem cells (GSCs) displayed resistance to cuproptosis with circadian variation of intracellular copper levels, unlike differentiated GBM cells (DGCs) or neural stem cells (NSCs). CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase Copper Transporting Alpha (ATP7A). Circadian control of copper homeostasis was mediated by core clock transcription factor, Basic helix-loop-helix ARNT-like protein 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back onto the circadian clock through SQSTM1 (sequestosome 1/p62)-mediated lysosomal degradation of BMAL1. Targeting cuproptosis and circadian clock or fatty acid desaturation generated synergistic anti-tumor effects. Thus, crosstalk between the circadian rhythm and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance.
2025-10-14 | GSE278671 | GEO
Project description:Tamoxifen resistance has been a major clinical problem and is accountable for relapse in about one third of ER positive breast cancer patients. Most of the recurrent patients will eventually receive chemotherapy. However, the chemosensitivity of these tamoxifen-resistant breast cancer patients has never been explored. In this study, we demonstrate that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, which results in the resistance to DNA-damaging chemotherapy including cisplatin and adriamycin , but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restored the sensitivity to cisplatin in tamoxifen-resistant cells. In addition, we identified that activated PI3K/AKT pathway in tamoxifen-resistant cells was responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors, BKM120 and BYL719, decreased the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitized them to cisplatin both in vitro and in xenografted mice. Higher BARD1 and BRCA1 expression was associated with poor prognosis of early breast cancer patients, especially the ones received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER positive breast cancer patients.
2021-03-15 | GSE111926 | GEO
Project description:α-Lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuels production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity, and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- 60 cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu, but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.
2024-05-23 | PXD045233 | Pride
Project description:Background & Aims: Patients with cholangiocarcinoma (CCA) have poor prognosis. Current first-line chemotherapy, including Cisplatin and Gemcitabine, provides limited survival benefits due to the development of chemoresistance. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. In this study, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents with unique polyelectrophilic properties, capable of inducing high frequency of double-strand DNA breaks, thereby inhibiting DNA repair and promoting cancer cell death. Methods: Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumour effects in both naïve and Cisplatin-resistant CCA cells, cancer-associated fibroblasts (CAFs), healthy cholangiocytes, and xenograft models. Results: Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity compared to Cisplatin in CCA cells. Unlike Cisplatin, Aurkines did not activate key proteins involved in single-strand DNA repair, such as ATR and CHK1 phosphorylation. Importantly, these compounds also triggered apoptosis in Cisplatin-resistant CCA cells and CAFs without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other Cisplatin-resistant cancers, such as breast and ovarian cancer. This selective action against malignant cells was attributed to differences in histone deacetylase (HDAC)-dependent DNA packaging between normal and cancer cells. In vivo, Aurkines inhibited the growth of both naïve and Cisplatin-resistant CCA tumours without adverse effects. Transport studies revealed that Aurkines were selectively taken up by transport proteins OCT1, OCT3, CTR1, and OATP1A2, whereas Cisplatin only modestly utilizes CTR1.
2025-11-10 | PXD061935 | Pride
Project description:Purpose: The goal of our study is to identify the differentially expressed genes between cispaltin sensitive and cisplatin resistance gastric cancer cell line. Methods: Transcriptome sequencing of cisplatin sensitive and cisplatin resistance KATOIII cells were generated by Illumina HiSeq TM, for triplicates Results : Using an optimized data analyzed workflow, we mapped 57773 genes and were found 5966 differentially expressed genes between cisplatin sensitive KATOIII and cisplatin resistance KATO/DDP cell lines.
2021-10-22 | GSE186205 | GEO
Project description:Breast cancers lacking receptors for estrogen, progesterone or HER2 on their cell surface are called triple-negative breast cancers (TNBCs). TNBCs account for ~15-20% of all invasive breast cancers and do not benefit from anti-hormonal or anti-HER2 treatments. Although patients with TNBC can initially respond to chemotherapy, they do have worse overall prognosis compared to other breast cancer subtypes. Unfortunately, TNBCs lack clear targetable ‘driver’ oncogenes. Thus, there is an unmet need for strategies to improve the therapeutic options for these patients. We used microarrays to assess differences in gene expression in triple-negative breast cancer cells in response to the platinum-based chemotherapeutic agent cisplatin. The purpose was to find drug induced changes in gene expression level that could differentiate cisplatin sensitive from cisplatin resistant TNBC cell lines.
2017-08-26 | GSE103115 | GEO
Project description:To determine the signaling networks that are dysregulated in platinum-resistant ovarian cancer, gene expression data were obtained from, and compared between, the ovarian cancer cell line, A2780, and its cisplatin-resistant derivative, A2780cis. Gene expression data from a cisplatin-sensitive ovarian cancer cell line (A2780) were collected and compared to gene expression data from a cisplatin-resistant cell line (A2780cis). 6 independent experiments were completed for both the sensitive and resistant cell lines.
2011-11-05 | E-GEOD-33482 | biostudies-arrayexpress