Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer
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...
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doaj-113b0593f3264cb1b883e0efb6e884892020-11-27T07:53:49ZengMDPI AGCells2073-44092020-11-0192535253510.3390/cells9122535Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate CancerShiv Verma0Eswar Shankar1E. Ricky Chan2Sanjay Gupta3Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USAInstitute of Computational Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USAAndrogen 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 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 <i>SLC12A5</i>, <i>SLC25A17</i>, and <i>SLC27A6</i> 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.https://www.mdpi.com/2073-4409/9/12/2535enzalutamide resistancecastration resistant prostate cancermetabolic reprogrammingsolute carrier proteins |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shiv Verma Eswar Shankar E. Ricky Chan Sanjay Gupta |
spellingShingle |
Shiv Verma Eswar Shankar E. Ricky Chan Sanjay Gupta Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer Cells enzalutamide resistance castration resistant prostate cancer metabolic reprogramming solute carrier proteins |
author_facet |
Shiv Verma Eswar Shankar E. Ricky Chan Sanjay Gupta |
author_sort |
Shiv Verma |
title |
Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer |
title_short |
Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer |
title_full |
Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer |
title_fullStr |
Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer |
title_full_unstemmed |
Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer |
title_sort |
metabolic reprogramming and predominance of solute carrier genes during acquired enzalutamide resistance in prostate cancer |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-11-01 |
description |
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 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 <i>SLC12A5</i>, <i>SLC25A17</i>, and <i>SLC27A6</i> 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. |
topic |
enzalutamide resistance castration resistant prostate cancer metabolic reprogramming solute carrier proteins |
url |
https://www.mdpi.com/2073-4409/9/12/2535 |
work_keys_str_mv |
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1724414103726850048 |