Abstract
Although second generation endocrine therapies have significantly improved survival, castration-resistant prostate cancer (CRPC) cells are eventually able to escape available hormonal treatments due to reactivation of androgen receptor (AR) signaling. Identification of novel, non-classical and druggable AR-target genes may provide new approaches to treat CRPC. Our previous analyses suggested that Aurora kinase A (AURKA) is regulated by androgens in prostate cancer cells that express high levels of AR. Here, we provide further evidence that AURKA is significantly overexpressed in AR-positive CRPC samples carrying amplification of AR gene and/or expressing AR in high levels. We also demonstrate androgen-induced AR binding in the intronic region of AURKA. The expression of AURKA is increased upon androgen stimulation in LNCaP-ARhi cells that express high levels of AR. The growth of the cells was also significantly inhibited by an AURKA specific inhibitor, alisertib (MLN8237). Together, these findings suggest that the expression of AURKA is regulated by androgen in prostate cancer cells that highly express AR, emphasizing its potential as a therapeutic target in patients with CRPC.
Highlights
Androgens and androgen receptor (AR) are known to be important drivers of prostate cancer progression[1,2]
In our earlier work18,we identified a set of 54 genes which we prioritized based on association of their expression with disease outcome and presence of prostate cancer specific AR binding sites (ARBSs) (Supplementary Table S1)
We have previously shown that the expression of Aurora kinase A (AURKA) is increased with androgen stimulation in LNCaP-ARhi cells expressing high levels of AR18 (Supplementary Figure S2), and Chromatin immunoprecipitation (ChIP)-seq analyses have indicated a putative prostate cancer specific ARBS in the promoter as well as in the intronic region of the gene[20,21,22,23] (Supplementary Table S1, Supplementary Figure S3)
Summary
Androgens and androgen receptor (AR) are known to be important drivers of prostate cancer progression[1,2]. It has been suggested that 10 to 25% of advanced AR-positive prostate cancers will become AR-negative NEPC2,7. Aurora kinase A (AURKA) is a serine-threonine kinase that functions in mitotic spindle formation and chromosome segregation[11,12,13,14,15,16] It has oncogenic properties when aberrantly expressed, inducing aneuploidy and cell transformation[11,13,15,16]. AURKA has been shown to be highly expressed, especially in AR-negative NEPC6 and in basal cell-like breast cancers[17]. A recent study by Pomerantz et al.[23] suggested that the intronic ARBS of AURKA is a prostate cancer-specific AR binding event. We studied the effect of AURKA specific inhibition in CRPC cells highly expressing AR
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