Abstract
The major challenge in castration-resistant prostate cancer (CRPC) remains the ability to predict the clinical responses to improve patient selection for appropriate treatments. The finding that androgen deprivation therapy (ADT) induces alterations in the androgen receptor (AR) transcriptional program by AR coregulators activity in a context-dependent manner, offers the opportunity for identifying signatures discriminating different clinical states of prostate cancer (PCa) progression. Gel electrophoretic analyses combined with western blot showed that, in androgen-dependent PCa and CRPC in vitro models, the subcellular distribution of spliced and serine-phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) isoforms can be associated with different AR activities. Using mass spectrometry and bioinformatic analyses, we showed that the protein sets of androgen-dependent (LNCaP) and ADT-resistant cell lines (PDB and MDB) co-immunoprecipitated with hnRNP K varied depending on the cell type, unravelling a dynamic relationship between hnRNP K and AR during PCa progression to CRPC. By comparing the interactome of LNCaP, PDB, and MDB cell lines, we identified 51 proteins differentially interacting with hnRNP K, among which KLK3, SORD, SPON2, IMPDH2, ACTN4, ATP1B1, HSPB1, and KHDRBS1 were associated with AR and differentially expressed in normal and tumor human prostate tissues. This hnRNP K–AR-related signature, associated with androgen sensitivity and PCa progression, may help clinicians to better manage patients with CRPC.
Highlights
In the last years, experimental evidence has supported the role of the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) development
Using mass spectrometry and bioinformatic analyses, we showed that the protein sets of androgen-dependent (LNCaP) and androgen deprivation therapy (ADT)-resistant cell lines (PDB and MDB) co-immunoprecipitated with heterogeneous nuclear ribonucleoprotein K (hnRNP K) varied depending on the cell type, unravelling a dynamic relationship between hnRNP K and AR during prostate cancer (PCa) progression to CRPC
By comparing the interactome of LNCaP, PDB, and MDB cell lines, we identified 51 proteins differentially interacting with hnRNP K, among which KLK3, SORD, SPON2, IMPDH2, ACTN4, ATP1B1, HSPB1, and KHDRBS1 were associated with AR and differentially expressed in normal and tumor human prostate tissues
Summary
Experimental evidence has supported the role of the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) development. Since multiple pathways are involved in CRPC development and progression, it is evident that therapies, to be useful, should selectively target driving molecular alterations at a specific stage of PCa evolution. For this purpose, we explored the possibility of developing a signature for identifying PCa and CRPC subtypes with different androgen responsiveness. Et al [18] underlined the importance of the adaptive phenotype acquired during ADT leading to cellular reprogramming that resulted in tumor heterogeneity and different AR status To reproduce this behavior, we obtained the androgen-resistant cell lines PDB and MDB by treating LNCaP cell line for over one year with the anti-androgen bicalutamide (BIC) in the presence or absence of 5-α-dihydrotestosterone (DHT), respectively. OveOravlelr,atlhl,etsheersesruelstusltssusguggegsetstthtahtathhnnRRNNPPKKiinn prostatee ccaanncceerrcceelllllilninesesisisliklieklyeltyotaoctaacst ans aAnRAR trantsrcarnipstciroipntailocnoalllacboolrlabtoorrathtoart rtehgaut laretegsuAlaRtesacAtivRityactthivroituyghthdroifufegrhendtimffeorleencut lmaromleeccuhlaarnimsmecshdaenpisemndsing on cdelelpdeinffdeirnegnotinatcieolnl ,dsiuffperpeonrttiiantigotnh, esuhpyppoortthinegsitshoefhtyhpeointhveoslivs eomf tehnetionfvohlnvRemNePnKt oifnhAnRDNTPreKsiisntaAnDceT. resistance
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