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.

Expression of lipid transport‐associated genes in lipid‐deprived cancer cells

“…On the other hand, at the 24‐hr time‐point, many genes were consistently upregulated in at least four cell lines. Table 1 displays the list of these genes, the information on family, molecular function ligands (lipid transport‐associated), subcellular localization, and cancer‐associated expression patterns of their encoded proteins are also provided (Carrara et al., 2018; Chen et al., 2020; Esau et al., 2016; Gordon et al., 2019; D. Jiang et al., 2020; Koochekpour et al., 2007; Swanton et al., 2007; Thorsen et al., 2011; Verma et al., 2020; Yang, He, et al., 2019; M. Zhang, Xiang, et al., 2020; Zheng et al., 2018). It was observed that STARD4, OSBPL9 LDLR, and SCARB1 genes were significantly upregulated in all the LPDS‐treated (24 hr) cell lines, whereas CERT1, OSBPL5, OSBPL1A, APOLD1, APOL5, CTEP, PSAP, CFHR4, APOO, and SLC27A6 were upregulated in at least four of the five cell lines (Table 1 and Figure 2).…”

“…Table 1 displays the list of these genes, the information on family, molecular function ligands (lipid transport-associated), subcellular localization, and cancer-associated expression patterns of their encoded proteins are also provided (Carrara et al, 2018;Chen et al, 2020;Esau et al, 2016;Gordon et al, 2019;D. Jiang et al, 2020;Koochekpour et al, 2007;Swanton et al, 2007;Thorsen et al, 2011;Verma et al, 2020;Yang, He, et al, 2019;M. Zhang, Xiang, et al, 2020;Zheng et al, 2018).…”

Identification of solute-carrier family 27A molecules (SCL27As) as a potential biomarker of ovarian cancer based on bioinformatics and experiments

“…A study in breast cancer has shown that the expression level of SLC27A6 in breast cancer tissues and breast cancer cells is significantly lower than that in normal breast tissues and breast cells (30). In addition, SLC27A6 was confirmed to be related to enzalutamide resistance in prostate cancer (31). However, the clinical value of SLC27A6 in ovarian cancer is unclear.…”

Prostate Cancer Progression: as a Matter of Fats

“…FATPs expression is highly heterogeneous in PCa tissues and cell lines and it varies across databases and detection methodologies ( 64 , 74 ). The expression of FATP-6 is increased in enzalutamide-resistant LNCaP cells compared to the parental cells but no association with prognosis was observed in the clinical setting ( 75 ). Thus, further investigation on the role of FATP1-6 in PCa progression is required.…”