title: Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling.
abstract: Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens in vitro using platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance.
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Zaslavsky
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gloeckner-Kalousek
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Adams
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Harene
authors.initials: H
authors.lastname: Venghatakrishnan
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Hangwen
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI; Departments of Internal Medicine and Biomedical Engineering, Biointerfaces Institute and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: Department of Urology, Division of Urologic Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI. Electronic address: gpalapat@med.umich.edu.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Palapattu
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone