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Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer.

ABSTRACT: Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi^®, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation. Next-Gen sequencing detected 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells, compared to their parental counterparts. A subset of differentially expressed genes were validated by qRT-PCR. Analysis by the i-pathway revealed membrane transporters including solute carrier proteins, ATP-binding cassette transporters, and drug metabolizing enzymes as the most prominent genes dysregulated in resistant cell lines. RNA-Seq data demonstrated predominance of solute carrier genes SLC12A5, SLC25A17, and SLC27A6 during metabolic reprogramming and development of drug resistance. Upregulation of these genes were associated with higher uptake of lactic/citric acid and lower glucose intake in resistant cells. Our data suggest the predominance of solute carrier genes during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment, thus signifying them as potentially attractive therapeutic targets.

SUBMITTER: Verma S

PROVIDER: S-EPMC7759897 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer.

Verma Shiv S Shankar Eswar E Chan E Ricky ER Gupta Sanjay S

Cells 20201124 12

Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi<sup>®</sup>, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic pr ...[more]

PMID: 33255236

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Project description:Genome-wide microarray analyses revealed that during biological activation of systemic acquired resistance (SAR) in Arabidopsis, the transcript levels of several hundred plant genes were consistently up- (SAR(+) genes) or down-regulated (SAR(-) genes) in systemic, non-inoculated leaf tissue. This transcriptional reprogramming fully depended on the SAR regulator FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1). Functional gene categorization showed that genes associated with salicylic acid (SA)-associated defenses, signal transduction, transport, and the secretory machinery are overrepresented in the group of SAR(+) genes, and that the group of SAR(-) genes is enriched in genes activated via the jasmonate (JA)/ethylene (ET)-defense pathway, as well as in genes associated with cell wall remodeling and biosynthesis of constitutively produced secondary metabolites. This suggests that SAR-induced plants reallocate part of their physiological activity from vegetative growth towards SA-related defense activation. Alignment of the SAR expression data with other microarray information allowed us to define three clusters of SAR(+) genes. Cluster I consists of genes tightly regulated by SA. Cluster II genes can be expressed independently of SA, and this group is moderately enriched in H2O2- and abscisic acid (ABA)-responsive genes. The expression of the cluster III SAR(+) genes is partly SA-dependent. We propose that SA-independent signaling events in early stages of SAR activation enable the biosynthesis of SA and thus initiate SA-dependent SAR signaling. Both SA-independent and SA-dependent events tightly co-operate to realize SAR. SAR(+) genes function in the establishment of diverse resistance layers, in the direct execution of resistance against different (hemi-)biotrophic pathogen types, in suppression of the JA- and ABA-signaling pathways, in redox homeostasis, and in the containment of defense response activation. Our data further indicated that SAR-associated defense priming can be realized by partial pre-activation of particular defense pathways.

Dataset Information

Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer.

Publications

Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer.

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