Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235366 | GEO | 2023/08/08
REPOSITORIES: GEO
Similar Datasets
Project description:Cisplatin resistance remains a major obstacle limiting the effectiveness of chemotherapy in cervical cancer. However, the underlying mechanism of cisplatin resistance is still unclear.
2023-08-08 | GSE235466 | GEO
Project description:Cervical cancer is the one of the most prevalent types of cancers in women and is the second highest cause of death in women aged 20-39. The most common chemotherapy for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments. This highlights the need to explore different therapeutic approaches for cervical cancer treatment. We found that inhibitors targeting the enzyme Poly (ADP-ribose) Polymearse (PARP)-1 can attenuate cell growth of cervical adenocarcinoma and squamous cell carcinoma. Furthermore, combinatorial therapy of PARP inhibitors (PARPi) with cisplatin increases the cisplatin-mediated cell toxicity in cervical cancer cells. This is accompanied by a rewiring of the transcriptome in response to the cisplatin and PARPi together. Surprisingly, we observed that the Fos gene is upregulated in the dual treatment condition leading to the subsequent induction of its target genes. Importantly, increased the expression of Fos is sufficient to hinder cervical cancer growth. We conclude that by inducing Fos expression, PARPi treatment with cisplatin leads to inhibition of cervical cancer.
2022-08-02 | GSE176326 | GEO
Project description:Ixr1 is a Saccharomyces cerevisiae HMGB protein that regulates the transcription of genes related to the response to changes normoxia-hypoxia, oxidative stress response or in the readaptation of catabolic and anabolic fluxes during oxygen limitation. Besides, Ixr1 binds to cisplatin-DNA adducts with high affinity. It is known that cancerous cells usually acquire resistance against the drug after the initial treatment, thus limiting its effectiveness. Yeast has been used as an easy-handled eukaryotic model to find genes related to cisplatin responsiveness and IXR1 is one among those that increase sensitivity. In this work, transcriptome analyses have been done to understand the regulatory roles of Ixr1 in absence or presence of cisplatin. Ixr1 behaves in yeast as a master regulator of other transcriptional factors, which respond to external stimuli and control cell growth, and proliferation. Diverse approaches including qPCR, ChIP and measure of 18S and 25S rRNAs confirm a function of Ixr1 in the control of ribosome biogenesis. Furthermore, several connections between this control, the TOR signaling pathway and cisplatin resistance in ixr1Δ mutants were found.
2018-02-21 | GSE101080 | GEO
Project description:A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. More than 80% of metastatic TGCT patients are cured with cisplatin-based chemotherapy. However, resistance can occur, which results in poor outcomes. The mechanisms of cisplatin hypersensitivity and resistance in these tumors and embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin acquired resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant alterations shared between resistant cells regardless of their parental origin. This included a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination and expression of BMI1. Importantly repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function could be a viable approach to overcome treatment failure.
2019-11-11 | GSE129696 | GEO
Project description:Infection with oncogenic human papillomavirus (HPV) is a major cause for the development of cervical cancer, which is mainly driven by the expression of the HPV E6 and E7 oncoproteins. We uncovered that the concentration levels of the putative tumor suppressor Dickkopf-1 (Dkk1) are restricted in cervical cancer cells by HPV E6 expression due to the E6-mediated proteolytic degradation of p53, which is a transcriptional regulator of Dkk1. Moreover, we found that Dkk1 is critically involved in the pro-apoptotic Cisplatin response of these cells, as Dkk1 repression was associated with an increased resistance towards the chemotherapeutic compound. This could be of high relevance for cervical cancer treatments, which usually involve Cisplatin for standard care. Although Dkk1 is a major antagonist of the canonical Wnt signaling, the differential response towards Cisplatin observed in Dkk1-depleted cells was not associated to an activation of this pathway. To elucidate alternative underlying mechanisms, we performed Affymetrix Gene Expression analyses comparing the transcriptome of Cisplatin-treated parental HeLa to CRISPR/Cas9-generated Dkk1 knockout (KO) HeLa cells. These revealed that Dkk1 depletion is linked to an impairment of the pro-apoptotic JNK/AP-1 pathway in cervical cancer cells, suggesting that Dkk1 drives Cisplatin-mediated apoptosis via activation of this signaling hub.
2022-08-16 | GSE200748 | GEO
Project description:Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting ROS accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated SLC1A5 and GLS expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
2023-08-07 | GSE239911 | GEO
Project description:Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, subsequently resulting in a poor long-term prognosis. To model the onset of drug resistance, we measured gene expression alterations associated with cisplatin resistance. We treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After 5 cycles of drug selection, the isogenic drug-sensitive (parental A2780) and -resistant (Round5 A2780) cell lines were subjected to mRNA expression microarray analyses.
2009-04-17 | E-GEOD-15372 | biostudies-arrayexpress
Project description:Cisplatin is a potent chemotherapeutic drug, widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, such as nephrotoxicity and chemotherapy-induced peripheral neuropathy. Therefore, there is an urgent medical need to identify novel strategies that would limit cisplatin-induced toxicity. In the present study, we provide evidence that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) significantly protects from cisplatin-induced nephrotoxicity and neuropathic pain in experimental models of acute and sub-chronic cisplatin intoxication. Importantly, we also demonstrate that the anti-tumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and even potentiated at the molecular level. Altogether, the present results support the use of istradefylline as a new valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.
2022-09-12 | GSE179246 | GEO
Project description:Cisplatin is a potent chemotherapeutic drug, widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, such as nephrotoxicity and chemotherapy-induced peripheral neuropathy. Therefore, there is an urgent medical need to identify novel strategies that would limit cisplatin-induced toxicity. In the present study, we provide evidence that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) significantly protects from cisplatin-induced nephrotoxicity and neuropathic pain in experimental models of acute and sub-chronic cisplatin intoxication. Importantly, we also demonstrate that the anti-tumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and even potentiated at the molecular level. Altogether, the present results support the use of istradefylline as a new valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.
2022-09-12 | GSE179245 | GEO
Project description:Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, subsequently resulting in a poor long-term prognosis. To model the onset of drug resistance, we measured gene expression alterations associated with cisplatin resistance.
2009-04-17 | GSE15372 | GEO