Dataset Information

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer.

ABSTRACT: Background:Resistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success. Methods:Xenografts from two human PCa cell lines (VCaP and CWR22) were established in male severe combined immunodeficiency mice, and MTX was administered, with or without concurrent castration, three times a week until tumors relapsed. Microarray technology was used to screen for differentially expressed genes (DEGs) in androgen-independent, MTX-resistant PCa xenografts. Gene expression profiles of MTX-treatment xenografts and their respective parental cell lines were performed using an Agilent whole human genome oligonucleotide microarray and analyzed using Ingenuity Pathway Analysis software. Results:A total of 636 genes were differentially expressed (fold change ?1.5; P<0.05) in MTX-resistant castration-resistant prostate cancer (CRPC) xenografts. Of these, 18 were selected to be validated and showed that most of these genes exhibited a transcriptional profile similar to that seen in the microarray (Pearson's r=0.87). Western blotting conducted with a subset of genes deregulated in MTX-resistant CRPC tumors was shown through network analysis to be involved in androgen synthesis, drug efflux, ATP synthesis, and vascularization. Conclusion:The present data provide insight into the genetic alterations underlying MTX resistance in androgen-independent PCa and highlight potential targets to improve therapeutic outcomes.

SUBMITTER: Zhu S

PROVIDER: S-EPMC6322516 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer.

Zhu Sha S Jiang Lili L Wang Liuyan L Wang Lingli L Zhang Cong C Ma Yu Y Huang Tao T

Cancer management and research 20190103

<h4>Background</h4>Resistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success.<h4>Methods</h4>Xenografts from two human PCa cell lines (VCaP and CWR22) were established in male severe combined immunodeficiency mice, and MTX was administered, with or without concurrent castration, three times a week until tumors relapsed. Microarray technology was used to screen for diffe ...[more]

PMID: 30655694

Similar Datasets

Project description:BackgroundCastration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.ResultsTreatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.ConclusionsCollectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.

Dataset Information

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer.

Publications

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets