title: 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.
authors.affiliation: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Current address: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Izhar
authors.initials: I
authors.lastname: Batth
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Huiyoung
authors.initials: H
authors.lastname: Yun
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Suleman
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Current address: Life Sciences Division, Lawrence Berkley National Laboratory, Berkley, CA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Meng
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Osmulski
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Tim Hui-Ming
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Roble
authors.initials: R
authors.lastname: Bedolla
authors.affiliation: Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Profit
authors.affiliation: Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Reddick
authors.affiliation: Department of Urology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.|Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.|Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX, USA.|The University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Addanki
authors.initials: A
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: FLIP; MST1R; RON; apoptosis; castrate resistant prostate cancer