Project description:Purpose: Androgen-deprivation therapy is the standard treatment for prostate cancer but fails in hormone-refractory prostate cancer. The anti-inflammatory plant Wedelia chinensis is rich in luteolin, apigenin, and wedelolactone that act synergistically to suppress androgen receptor activity in prostate cancer. Here, we evaluated the systemic antitumor effects of a standardized and effect-optimized Wedelia chinensis herbal extract (WCE) on hormone-refractory prostate cancer. Methods: Hormone-refractory PC-3 orthotopic tumor mouse models were orally administered with WCE. The tumor transcriptomes were studied using RNA sequencing and Ingenuity Pathway Analysis to identify the molecular mechanisms. Results: WCE significantly attenuated tumor growth and metastasis in orthotopic PC-3 xenografts. Transcriptomic analysis of genome-wide gene expression in the tumors revealed that WCE suppressed the expression of HIF1α, IKKα/β phosphorylation, and the downstream cytokines/chemokines. Conclusions: A standardized preparation of Wedelia chinensis improved prostate cancer therapy through repressing NFκB-mediated cytokine expression in tumor cells and modulating the inflammatory tumor microenvironment. These data suggest that WCE functions through immunomodulation and has potential application as an adjuvant agent for the treatment of castration-resistant prostate cancer.
Project description:Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment, and its progression mechanism is not fully uncovered. This study aims to clarify the role and mechanism of Human antigen R (HuR) as a therapeutic target for CRPC progression.
Project description:Translational regulation plays a critical role in cell growth and proliferation, and its dysregulation results in cancer. Aberrant expression of the mRNA 5’cap-binding protein, eIF4E, has been implicated in cancer development and progression. eIF4E activity is promoted by phosphorylation. Here we show that “knock-in” mice in which eIF4E cannot be phosphorylated are resistant to tumorigenesis in a prostate cancer model. We identify multiple candidate genes involved in the resistance to oncogenic transformation. Importantly, phosphorylation of eIF4E is increased in hormone-refractory prostate cancer, the deadliest stage of the disease. Our results highlight eIF4E phosphorylation as a critical event in tumorigenesis. Comaparison of total RNA and polysomal RNA from mouse embryo fibroblasts derived from WT and eIF4E-KI (non phosphorylatable eIF4E) mice
Project description:Therapies targeting the androgen receptor are critical for treatment of hormone refractory prostate cancer. We have previously demonstrated that Ebp1, a protein isolated by its ability to bind ErbB3, is a downstream effector of heregulin activated pathways and an AR corepressor. As Ebp1 is decreased in preclinical models of hormone refractory prostate cancer, we studied the ability of Ebp1 to mitigate the hormone refractory phenotype. As we previously found that Ebp1 affected the expression of some androgen receptor target genes, we sought to determine a full spectrum of genes changed using an unbiased appraoch by microarry analysis. Experiment Overall Design: A hormone independent cell line C81 was derived from LNCaP cells by long term passage and was a kind gift of Dr. Lin (University of Nebraska). C81 cell were transfected with a vector control or EBP1 expression plasmids and mass cultures selected. RNA was collected from logaritmically growing cultures.
Project description:Therapies targeting the androgen receptor are critical for treatment of hormone refractory prostate cancer. We have previously demonstrated that Ebp1, a protein isolated by its ability to bind ErbB3, is a downstream effector of heregulin activated pathways and an AR corepressor. As Ebp1 is decreased in preclinical models of hormone refractory prostate cancer, we studied the ability of Ebp1 to mitigate the hormone refractory phenotype. As we previously found that Ebp1 affected the expression of some androgen receptor target genes, we sought to determine a full spectrum of genes changed using an unbiased appraoch by microarry analysis.
Project description:To characterize the molecular features of clinical (Hormone-Refractory Prostate Cancers) HRPCs, we generated the precise gene-expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdisection. Keywords: disease status analysis
Project description:Translational regulation plays a critical role in cell growth and proliferation, and its dysregulation results in cancer. Aberrant expression of the mRNA 5’cap-binding protein, eIF4E, has been implicated in cancer development and progression. eIF4E activity is promoted by phosphorylation. Here we show that “knock-in” mice in which eIF4E cannot be phosphorylated are resistant to tumorigenesis in a prostate cancer model. We identify multiple candidate genes involved in the resistance to oncogenic transformation. Importantly, phosphorylation of eIF4E is increased in hormone-refractory prostate cancer, the deadliest stage of the disease. Our results highlight eIF4E phosphorylation as a critical event in tumorigenesis.
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. To investigate the AR signaling, we performed RNA sequence analysis in AR positive prostate cancer cell line, LNCaP. In addition, we used hormone-refractory prostate cancer model cells, Bicalutamide-resistant (BicR) to explore the differences of androgen signaling in prostate cancer progression. Short RNA sequence analysis of androgen-regulated miRNAs in two prostate cancer cells
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. To investigate the AR signaling, we performed CaP analysis of gene expression (CAGE) analysis in AR positive prostate cancer cell line, LNCaP. In addition, we used hormone-refractory prostate cancer model cells, Bicalutamide-resistant (BicR) to explore the differences of androgen signaling in prostate cancer progression. CAGE analysis of androgen-regulated transcripts in two prostate cancer cells