Gene expression profiling of MDA-MB-231 cells treated Compound 28, a CDK9 degrader
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ABSTRACT:
PROVIDER: PRJNA1189447 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31443314_1.fastq.gz | Fastqsanger.gz | |||
| SRR31443314_2.fastq.gz | Fastqsanger.gz | |||
| SRR31443315_1.fastq.gz | Fastqsanger.gz | |||
| SRR31443315_2.fastq.gz | Fastqsanger.gz | |||
| SRR31443316_1.fastq.gz | Fastqsanger.gz |
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Project description:Triple-negative breast cancer (TNBC) is highlyaggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting CDK9 to remodel transcriptional regulation shows great promisein cancer therapy. We synthesized new series of heterobifunctional molecules ashighly selective and efficacious CDK9 degraders, enabling potentinhibition of TNBC cell growth and rapidly targeted degradationof CDK9. Moreover, the CDK9 degrader (compound 28) was used to treat on TNBC cell lines and the gene expression profile was performed by RNA-seq.
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Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
2017-09-01 | GSE89385 | GEO
Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
2017-09-01 | GSE89384 | GEO
Project description:MiR-544 was inhibited by either a miR-544 antagomir or compound 1 under hypoxic conditions in MDA-MB-231 cells MiRNA microarray was utilized to examine the specificity of 1 for miR-544. 3 MDA-MB-231 samples treated with a miR-544 antagomir or compound 1 were subjected to hypoxia for a period of 5 days. After 5 days, samples were pooled and subjected to miRNA microarray analysis.
2014-12-23 | E-GEOD-64436 | biostudies-arrayexpress
Project description:In the past decades, altered Follistatin‑like 1 (FSTL1) expression has been documented in a variety of cancers, while its functional roles are poorly understood. Particularly in breast cancer, the expression of FSTL1 and its signaling pathway remain to be determined. In the present study, an elevated FSTL1 expression and a supressed cell proliferation were detected in a specific brain metastatic cell line MDA‑MB‑231‑BR (231‑BR), compared with its parental cell line MDA‑MB‑231. However, this protein was hardly detected in the other three breast cancer cell lines. Next, lentiviral vectors encoding FSTL1 or FSTL1 specific shRNAs were used to overexpress or knock down FSTL1 in MDA‑MB‑231 or 231‑BR, respectively (MDA‑MB‑231FSTL1 or 231‑BRsh FSTL1). Results showed that overexpression of FSTL1 inhibited MDA‑MB‑231 cell proliferation, while knockdown of FSTL1 in 231‑BR cells promotes cell proliferation, compared with their corresponding control groups. These results were further confirmed in nude mouse xenografts. The tumor volume in 231‑BR cell-bearing mice was significantly smaller than that of MDA‑MB‑231 group, and reduction of tumor volume was detected in MDA‑MB‑231FSTL1 cell-bearing mice compared with the control group. Previous studies revealed that TGF‑β-Smad2/3 signaling pathway was activated in 231‑BR and MDA‑MB‑231FSTL1 cells, which may contribute to the inhibited cell proliferation. In addition, Smad3 knockdown could restore the inhibition of cell proliferation induced by FSTL1 overexpression in MDA‑MB‑231FSTL1 cells, indicating that the anti‑proliferative effect of FSTL1 overexpression may be associated with Smad3 involved TGF‑β signaling pathway regulation. This study identified FSTL1 as an inhibitor of cell proliferation in MDA‑MB‑231 and 231‑BR cell lines, which may provide new insights into the development and management of breast cancer.
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Project description:BackgroundBreast cancer remains a leading cause of death in women worldwide. Although breast cancer therapies have greatly advanced in recent years, many patients still develop tumour recurrence and metastasis, and eventually succumb to the disease due to chemoresistance. Citral has been reported to show cytotoxic effect on various cancer cell lines. However, the potential of citral to specifically target the drug resistant breast cancer cells has not yet been tested, which was the focus of our current study.MethodsThe cytotoxic activity of citral was first tested on MDA-MB-231 cells in vitro by MTT assay. Subsequently, spheroids of MDA-MB-231 breast cancer cells were developed and treated with citral at different concentrations. Doxorubicin, cisplatin and tamoxifen were used as positive controls to evaluate the drug resistance phenotype of MDA-MB-231 spheroids. In addition, apoptosis study was performed using AnnexinV/7AAD flowcytometry. Aldefluor assay was also carried out to examine whether citral could inhibit the ALDH-positive population, while the potential mechanism of the effect of citral was carried out by using quantitative real time- PCR followed by western blotting analysis.ResultsCitral was able to inhibit the growth of the MDA-MB-231 spheroids when compared to a monolayer culture of MDA-MB-231 cells at a lower IC50 value. To confirm the inhibition of spheroid self-renewal capacity, the primary spheroids were then cultured to additional passages in the absence of citral. A significant reduction in the number of secondary spheroids were formed, suggesting the reduction of self-renewal capacity of these aldehyde dehydrogenase positive (ALDH+) drug resistant spheroids. Moreover, the AnnexinV/7AAD results demonstrated that citral induced both early and late apoptotic changes in a dose-dependent manner compared to the vehicle control. Furthermore, citral treated spheroids showed lower cell renewal capacity compared to the vehicle control spheroids in the mammosphere formation assay. Gene expression studies using quantitative real time PCR and Western blotting assays showed that citral was able to suppress the self-renewal capacity of spheroids and downregulate the Wnt/β-catenin pathway.ConclusionThe results suggest that citral could be a potential new agent which can eliminate drug-resistant breast cancer cells in a spheroid model via inducing apoptosis.
| S-EPMC5809808 | biostudies-literature
Project description:MiR-544 was inhibited by either a miR-544 antagomir or compound 1 under hypoxic conditions in MDA-MB-231 cells MiRNA microarray was utilized to examine the specificity of 1 for miR-544.
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2022-11-30 | GSE188629 | GEO
Project description:Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions. Parental MDA-MB-231 cells and MDA-MB-231(SA) cells were cultured in cell culture flasks. RNA was isolated in order to compare the gene expression profiles of these cell variants. Total of two samples. No replicates.
| S-ECPF-GEOD-20085 | biostudies-other
Project description:Background: Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been used as an alternative cell death method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells are largely unknown. Methods: Paraptosis-inducing agents, CPYPP, cyclosporin, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. The xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. Results: CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R (PKR) in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. A xenograft mouse model with OECM-1 cells further confirmed the induction of paraptosis against tumor growth. Conclusions We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.
2024-06-20 | GSE262661 | GEO