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

Abstract

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.

Receptor tyrosine kinase recepteur d'origine nantais as predictive marker for aggressive prostate cancer in African Americans

“…Furthermore, levels of c‐FLIP are also elevated in human prostate tumors including castrate resistant tumors making it a clinically relevant target. Our findings that increased expression of AR, RON, and c‐FLIP in tumors is in line with published studies including our own . However, the present study to the best of our knowledge is the first report showing a correlation between RON/AR with ethnicity.…”

“…Previously, we showed that RON promotes PCa cell growth by functioning as a transcription factor to activate c-FLIP. 2 We recently demonstrated that RON is activated as an alternative by-pass signaling mechanism to compensate for the loss of AR under androgen-deprived conditions. These data suggest that under androgen-deprived conditions RON activates AR pathway leading to castrate-resistance.…”

“…Rabbit horseshoe radish peroxidase polymer and DAB chromogen were used as the ancillary system and hematoxylin was used for counterstaining (Biocare Medical, Concord, CA and DAKO North America Inc. Carpinteria, CA). As shown in Figure S1, human prostate cancer cell lines LNCaP, and 22Rv1obtained from American Type Culture Collection (Manassas, VA) were grown as described previously …”

“…Relative mRNA expression was normalized to β‐actin. Polymerase chain reaction (PCR) reactions were conducted with three biological replicates, each with three technical replicates as described previously . The primer sequences used are shown in Figure S1.…”

“…As shown in Figure S1, human prostate cancer cell lines LNCaP, and 22Rv1obtained from American Type Culture Collection (Manassas, VA) were grown as described previously. 2,17,18 2.3 | Semiquantitative evaluation of tissue staining and biomarker score and biomarker score TMAs containing 30 to 40% tumor was chosen for pathological evaluation. A pathologist (RR) blinded to the identity of samples evaluated staining of specific proteins.…”