title: Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells.
abstract: The tumour protein D52 isoform 1 (PC-1), a member of the tumour protein D52 (TPD52) protein family, is androgen-regulated and prostate-specific expressed. Previous studies confirmed that PC-1 contributes to malignant progression in prostate cancer with an important role in castration-resistant stage. In the present work, we identified its impact in mechanisms leading to neuroendocrine (NE) transdifferentiation. We established for long-term PC-1 overexpression an inducible expression system derived from the prostate carcinoma cell line LNCaP. We observed that PC-1 overexpression itself initiates characteristics of neuroendocrine cells, but the effect was much more pronounced in the presence of the cytokine interleukin-6 (IL-6). Moreover, to our knowledge, this is the first report that treatment with IL-6 leads to a significant upregulation of PC-1 in LNCaP cells. Other TPD52 isoforms were not affected. Proceeding from this result, we conclude that PC-1 overexpression enhances the IL-6-mediated differentiation of LNCaP cells into a NE-like phenotype, noticeable by morphological changes and increased expression of typical NE markers, like chromogranin A, synaptophysin or beta-3 tubulin. Immunofluorescent staining of IL-6-treated PC-1-overexpressing LNCaP cells indicates a considerable PC-1 accumulation at the end of the long-branched neuron-like cell processes, which are typically formed by NE cells. Additionally, the experimentally initiated NE transdifferentiation correlates with the androgen receptor status, which was upregulated additively. In summary, our data provide evidence for an involvement of PC-1 in NE transdifferentiation, frequently associated with castration resistance, which is a major therapeutic challenge in the treatment of advanced prostate cancer.
authors: Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.
authors: Tom
authors: T
authors: Moritz
authors: Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.
authors: Simone
authors: S
authors: Venz
authors: Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany. hjunker@uni-greifswald.de.
authors: Heike
authors: H
authors: Junker
authors: Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.|Laboratory of Chromatin Biochemistry, BESE Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia.
authors: Sarah
authors: S
authors: Kreuz
authors: Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany. rwalther@uni-greifswald.de.
authors: Reinhard
authors: R
authors: Walther
authors: Department of Urology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
authors: Uwe
authors: U
authors: Zimmermann
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015415:Biomarkers; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology*; D055099:Neuroendocrine Cells / Q000737:chemistry / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000072417:Protein Domains; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011944:Receptors, Androgen / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D015850:Interleukin-6; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; C114751:TPD52 protein, human
keywords: LNCaP; Neuroendocrine transdifferentiation; PC-1; PrLZ; Prostate cancer; TPD52