Oncotarget

Research Papers:

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

Izhar Batth, Huiyoung Yun, Suleman Hussain, Peng Meng, Pawel Osmulski, Tim Hui-Ming Huang, Roble Bedolla, Amanda Profit, Robert Reddick and Addanki Kumar _

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Oncotarget. 2016; 7:14048-14063. https://doi.org/10.18632/oncotarget.7287

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Abstract

Izhar Batth1,8, Huiyoung Yun2, Suleman Hussain2, Peng Meng1,7, Pawel Osmulski3, Tim Hui-Ming Huang3,5, Roble Bedolla1, Amanda Profit4, Robert Reddick4, Addanki Kumar1,2,3,5,6

1Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA

2Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA

3Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA

4Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA

5Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA

6The University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA

7Current address: Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, CA, USA

8Current address: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Addanki Kumar, e-mail: [email protected]

Keywords: castrate resistant prostate cancer, apoptosis, FLIP, RON, MST1R

Received: November 18, 2015     Accepted: January 29, 2016     Published: February 9, 2016

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.


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