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Oncotarget. 2016 Mar 22;7(12):14048-63. doi: 10.18632/oncotarget.7287.

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

Author information

1
Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.
2
Current address: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
4
Current address: Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, CA, USA.
5
Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
6
Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.
7
Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA.
8
The University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA.

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.

KEYWORDS:

FLIP; MST1R; RON; apoptosis; castrate resistant prostate cancer

PMID:
26872377
PMCID:
PMC4924697
DOI:
10.18632/oncotarget.7287
[Indexed for MEDLINE]
Free PMC Article

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