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.
Highlights
Prostate cancer is the second-leading cause of cancer-related mortality among men in the UnitedStates
Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) through medical or surgical castration is the mainstay treatment for patients with locally advanced and metastatic disease [1]
Androgen-responsive LNCaP cells were derived from a needle biopsy taken from the left supraclavicular lymph node metastasis and harbor point mutation at AR containing the threonine to alanine mutation of amino acid 877
Summary
Prostate cancer is the second-leading cause of cancer-related mortality among men in the UnitedStates. Cells 2020, 9, 2535 fails to induce the precise conformational changes after binding to AR, resulting in limited efficacy [3,4]. This has led to the development of second generation antiandrogens that prevent AR translocation to the nucleus and inhibit downstream signaling or androgen biosynthesis [5]. Reports from several randomized phase III clinical trials have shown increased survival [6], in patients with high tumor burden, when enzalutamide, a second generation antiandrogen, is started at the same time as initial ADT in a castration-sensitive environment [7]. Despite sustained response and initial benefit from enzalutamide, the majority of patients develop resistance and emergence of castration resistant prostate cancer (CRPC) [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
