title: Secretory leukocyte protease inhibitor is a survival and proliferation factor for castration-resistant prostate cancer.
abstract: Androgen receptor (AR)-mediated gene expression continues to have a critical role in promoting castration-resistant prostate cancer (CRPC) survival and growth even after androgen deprivation therapy. AR cistrome analyses in CRPC cells have identified a large number of AR target genes involved in proliferative and cell cycle-related functions, and hold promise for development of novel therapeutic approaches for CRPC. However, there is little understanding of how these genes function in vivo and what the clinical implications are. We previously reported that secretory leukocyte peptidase inhibitor (SLPI) is regulated by the AR in a ligand-independent manner in CRPC cells and required for CRPC cell proliferation under androgen-deprived conditions. SLPI is a secreted serine protease inhibitor, which is overexpressed in a number of cancers, including lung, breast and ovarian cancer, and involved in tumor progression. However, the oncogenic potential of SLPI in prostate cancer remains unknown. Here we provide the first evidence that SLPI is upregulated in a subset of CRPC cell lines and CRPC patient tumors. In addition, serum SLPI levels are significantly elevated in metastatic CRPC patients compared with hormone naive patients, raising the possibility that this could serve as a biomarker. We demonstrated that SLPI expression has functional significance, as it promotes CRPC cell survival and growth after androgen withdrawal in vivo and in vitro. Last, we demonstrated that the oncogenic effect of SLPI may be due to protection of growth factor progranulin from enzymatic cleavage or suppression of CRPC cell apoptosis independent of anti-protease activity of SLPI. These findings implicate SLPI as a potential biomarker of resistance to AR inhibition and therapeutic target for CRPC treatment.
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gui
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Gray
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Tinay
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rafiei
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Kibel
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jia
mesh_terms: D000728:Androgens / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D000077153:Progranulins; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000097:blood / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000728:Androgens; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011944:Receptors, Androgen; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor