The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small Cell Lung Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA497599 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8080970_1.fastq.gz | Fastqsanger.gz | |||
| SRR8080970_2.fastq.gz | Fastqsanger.gz | |||
| SRR8080980_1.fastq.gz | Fastqsanger.gz | |||
| SRR8080980_2.fastq.gz | Fastqsanger.gz | |||
| SRR8080961_1.fastq.gz | Fastqsanger.gz |
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Project description:Small cell lung cancer (SCLC), accounts for about 15 percent of all lung cancers, is a neuroendocrine type of carcinoma and is incredibly aggressive, with a dire diagnosis of 5% survival at 5 years. FDA-approved therapies for this disease are almost exclusively limited to chemotherapy and radiotherapy, to which resistance arises within months. Despite global sequencing efforts, few activating mutations have been discovered in SCLC tumors, and targetable alterations account for very small subsets of patients. Due to this lack of a strong oncogenic driver for conventional targeted therapy, SCLC has the potential to benefit from non-oncogene-addiction-based therapeutic approaches. We therefore focused on finding novel non-mutated pathways which could be targetable in SCLC. Restricting our search to kinases, a highly-targetable group of enzymes, we elucidated the active kinome of SCLC and upon identifying MEK5 as a SCLC-specific active kinase, further investigated the role of the MEK5-ERK5 kinase axis in this tumor type. We found that reduction in this axis in both human and murine SCLC cells causes increased susceptibility to apoptosis, and decreased subcutaneous tumor growth in vivo. Transcriptomic analysis of MEK5 and ERK5-knockdown cells showed downregulation of lipid metabolism pathways and SREBP target genes. Based on targeted lipidomics analyses of these same cells, which showed downregulated cholesterol ester species, we focused on the mevalonate arm of the SREBP pathway.
2021-10-17 | GSE121538 | GEO
Project description:We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells. This screen identified the MEK5-ERK5 axis as a critical player in TGFb-mediated EMT. Suppression of MEK5-ERK5 signaling completely prevented the morphological and molecular changes occurring during a TGFb-induced EMT and, conversely, forced highly metastatic breast cancer cells into a differentiated epithelial state. Inhibition of MEK5-ERK5 signaling also repressed breast cancer cell migration and invasion and substantially reduced lung metastasis without affecting primary tumor growth. The results suggest that the MEK5-ERK5 signaling axis plays an important role in the induction and maintenance of breast cancer cell migration and invasion and thus represents an exploitable target for the pharmacological inhibition of cancer cell metastasis.
2018-05-17 | GSE100403 | GEO
Project description:Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal and tissue-restricted deletions have profound effects on erythroid development, cardiac function and neurogenesis. In addition, depletion of ERK5 is anti-inflammatory and anti-tumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a non-catalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity, and delineate which can be pharmacologically targeted.
2016-09-09 | GSE86577 | GEO
Project description:To investigate the function of MEK5/ERK5 in the regulation of hPSC pluripotency, we processed MAP2K5DD (MEK5DD) overexpression H1 ESC line.
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Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in PC3 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.
2023-08-16 | GSE156401 | GEO
Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in DU145 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.
2023-08-16 | GSE156399 | GEO
Project description:ERK5 is a dual kinase-transcription factor, which contains an N-terminal kinase domain and transactivation domains in the C-terminal half. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions regarding the functional role of ERK5 kinase inhibitors. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the senescence-associated secretory phenotype (SASP), consequently leading to atherosclerosis. We showed that atherosclerosis was inhibited in ERK5 S496A (dephosphorylation mimic) knock-in (KI) mice. Furthermore, ERK5 S496 phosphorylation was required for not only SASP but also senescence-associated cell growth (SACG) observed in the plaque via upregulation of aryl hydrocarbon receptor (AHR). We also discovered a key effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) both inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism, in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation, and induces SACG and atherosclerosis.
2023-06-09 | GSE210949 | GEO
Project description:Background: Gq-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of cardiovascular function. Enhanced Gaq-mediated signaling plays an important role in cardiac hypertrophy and in the transition to heart failure. We have recently described that Gaq acts as an adaptor protein that facilitates PKCz-mediated activation of ERK5 in epithelial cells. Since the ERK5 cascade is known to be involved in cardiac hypertrophy, we have investigated the potential relevance of this pathway in Gq-dependent signaling in cardiac cells. Methodology/Principal Findings: We have explored the mechanisms involved in Gq-coupled GPCR-mediated stimulation of the ERK5 pathway and its functional consequences in cardiac hypertrophy using both cultured cardiac cells and an animal model of angiotensin- dependent induction of cardiac hypertrophy in wild-type and PKCz knockout mice. We find that PKC? is required for the activation of the ERK5 pathway by Gq-coupled GPCR in cardiomyocytes and in cardiac fibroblasts. Stimulation of ERK5 by angiotensin II is blocked upon pharmacological inhibition or siRNA-mediated silencing of PKCz in primary cultures of cardiac cells and in cardiomyocytes isolated from PKCz-deficient mice. Moreover, these mice do not develop cardiac hypertrophy upon chronic challenge with angiotensin II, as assessed by morphological, biomarker, electrocardiographic and global gene expression pattern analysis. Conclusion/Significance: Our data put forward that PKC? is essential for Gq- dependent ERK5 activation in cardiac cells and indicate a key cardiac physiological role for this recently described Gaq/PKCz/MEK5 signaling axis. Littermate wild-type and PKCz -/- male mice (32 weeks of age) were subjected to continuous infusion of angiotensin II (or PBS as a control) for 14 days, a well established model for the induction of cardiac hypertrohy
2012-01-10 | E-GEOD-29145 | biostudies-arrayexpress
Project description:Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. SIGNIFICANCE: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.
| S-EPMC7073279 | biostudies-literature
Project description:Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this particular MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth, colony-forming capacity, and caused a marked loss of tumor growth in vivo. Indeed, the transcriptomic profile in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration or motility, among others. Finally, among the various differentially expressed genes, Klf2, a direct target of the ERK5 pathway, is a key mediator of the biological effects of ERK5 in vitro and in vivo, as indicated by its specific interference. Therefore, our data suggest that the ERK5KLF2 signaling axis is an important determinant of 3MC-induced sarcomas and should be further studied in human sarcomas, especially those of muscular origin.
2022-08-03 | GSE199395 | GEO