Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer

Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear.

Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy.

Oncotarget. 2016 Feb 09 [Epub ahead of print]

Izhar Batth, Huiyoung Yun, Suleman Hussain, Peng Meng, Powel Osumulski, Tim Hui-Ming Huang, Roble Bedolla, Amanda Profit, Robert Reddick, Addanki Kumar

Department of Urology, San Antonio, TX, USA. , Department of Pharmacology, San Antonio, TX, USA. , Department of Pharmacology, San Antonio, TX, USA. , Department of Urology, San Antonio, TX, USA. , Department of Molecular Medicine, San Antonio, TX, USA. , Department of Molecular Medicine, San Antonio, TX, USA. , Department of Urology, San Antonio, TX, USA. , Department of Pathology, San Antonio, TX, USA. , Department of Pathology, San Antonio, TX, USA. , Department of Urology, San Antonio, TX, USA.

PubMed

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