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Article

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

by 1,2, 1,2, 3 and 1,2,4,5,6,*
1
Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
2
The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
3
Institute of Computational Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
4
Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA
5
Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA
6
Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(12), 2535; https://doi.org/10.3390/cells9122535
Received: 27 October 2020 / Revised: 13 November 2020 / Accepted: 21 November 2020 / Published: 24 November 2020
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. View Full-Text
Keywords: enzalutamide resistance; castration resistant prostate cancer; metabolic reprogramming; solute carrier proteins enzalutamide resistance; castration resistant prostate cancer; metabolic reprogramming; solute carrier proteins
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MDPI and ACS Style

Verma, S.; Shankar, E.; Chan, E.R.; Gupta, S. Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer. Cells 2020, 9, 2535. https://doi.org/10.3390/cells9122535

AMA Style

Verma S, Shankar E, Chan ER, Gupta S. Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer. Cells. 2020; 9(12):2535. https://doi.org/10.3390/cells9122535

Chicago/Turabian Style

Verma, Shiv, Eswar Shankar, E. Ricky Chan, and Sanjay Gupta. 2020. "Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer" Cells 9, no. 12: 2535. https://doi.org/10.3390/cells9122535

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