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RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

ABSTRACT: RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

PROVIDER: PRJNA811241 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18173262_1.fastq.gz	Fastqsanger.gz
	SRR18173262_2.fastq.gz	Fastqsanger.gz
	SRR18173263_1.fastq.gz	Fastqsanger.gz
	SRR18173263_2.fastq.gz	Fastqsanger.gz
	SRR18173264_1.fastq.gz	Fastqsanger.gz

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RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

Project description:The aim of this research was to confirm the regulatory effect of RUVBL1 on gene expression in castration resistant prostate cancer.

2022-03-02 | GSE197630 | GEO

Ligand-independent CXCR7 Activation of MAPK Signaling leads to Prostate Cancer Enzalutamide Resistance

Project description:The standard of care for patients with advanced form of prostate cancer, castration-resistant, now includes enzalutamide, a second generation antiandrogen. However, most of the treated patients will develop resistance to enzalutamide based therapy in around a year, succumbing to lethal disease. Investigating the transcriptome of enzalutamide-resistant prostate cancer cell lines, we identified CXCR7 as one of the most upregulated genes suggesting its role in advanced prostate cancer. CXCR7, known as an atypical G-coupled receptor, is engaged in many physiological and pathological processes. Here we show that in prostate cancer CXCR7 is tightly regulated by androgen receptor (AR), which directly binds to CXCR7 gene promoter and enhancer and represses its transcription. In turn, CXCR7 in prostate cancer reduces enzalutamide toxicity and promotes cell survival and invasiveness. We identified that CXCR7 forms an integral complex with ARRB2 and activates ERK1/2, eliciting pro-survival MAPK pathway. Enzalutamide treatment combined with MAPKK specific inhibitor, trametinib, reversed enzalutamide resistance in prostate cancer in vitro and in vivo. Taken together our findings highlight the critical role of CXCR7 in enzalutamide-resistant prostate cancer and open an avenue for developing novel anti-CXCR7 therapies to improve survival in patients with advanced prostate cancer.

2019-04-06 | GSE104935 | GEO

PDGFC facilitates enzalutamide resistance in prostate cancer through autocrine activation of the RAP1-MAPK pathway

Project description:Prostate cancer (PCa) is a highly heterogeneous malignant tumor within the male genitourinary system, characterized by its invasive and metastatic potential. Although the second-generation androgen receptor (AR) antagonist enzalutamide has shown therapeutic efficacy in PCa patients, enzalutamide resistance (EnzaR) will be inevitably develops and the underlying mechanisms are not fully understood. In this study, we confirmed that the expression of Platelet-Derived Growth Factor C (PDGFC) elevated in EnzaR PCa and promoted the proliferation of PCa in vitro and in vivo. Silencing PDGFC in EnzaR cells notably enhances the sensitivity of EnzaR PCa cells to enzalutamide, thereby inhibiting the progressive of PCa. Mechanistically, overexpressed PDGFC activates the PDGFR-RAP1-MAPK signaling cascade in an autocrine fashion within EnzaR cells. PDGFR inhibitors alone or combined with enzalutamide significantly suppressed the progression of EnzaR PCa xenografts. Additionally, we demonstrated that the transcription factor STAT4 binds to a specific DNA sequence in the PDGFC promoter region, which is essential for PDGFC upregulation. Collectively, our results confirmed the pivotal role of PDGFC in PCa cells developing resistant to enzalutamide therapy, suggesting that targeting PDGFC may serve as a promising therapeutic strategy for EnzaR PCa.

2026-01-30 | GSE287028 | GEO

CRAF dimerization with ARAF regulates KRAS driven tumors

Project description:KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. It has previously been shown that CRAF is required for growth of KRAS mutant lung tumors but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescued growth inhibition suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest. Treatment with low dose MEK or ERK inhibitor rescued the CRAF loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting dimerization or degrading CRAF may have therapeutic benefit.

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Project description:KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescued growth inhibition suggesting dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest, while treatment with low dose MEK or ERK inhibitor rescued the CRAF loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.

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Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors

Project description:Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors

2015-10-01 | GSE62645 | GEO

Expression data from prostate cancer cell lines C4-2B (enzalutamide sensitive) and C4-2B-MDVR (enzalutamide resistant) cells

Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.

2015-04-09 | E-GEOD-64143 | biostudies-arrayexpress

Ligand-independent CXCR7 Activation of MAPK Signaling leads to Prostate Cancer Enzalutamide Resistance

Project description:Ligand-independent CXCR7 Activation of MAPK Signaling leads to Prostate Cancer Enzalutamide Resistance

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FMNL2/SRC-mediated androgen receptor translocation into the nucleus promotes enzalutamide resistance of prostate cancer

Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa, and dasatinib could be an option.

2025-01-13 | PXD059539 | Pride

Targeting DNMTs to overcome enzalutamide resistance in prostate cancer

Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a re-sensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair and mRNA splicing. Combination treatment of Decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.

2021-09-22 | GSE184168 | GEO

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