Tumor Biology

, Volume 37, Issue 8, pp 10435–10446 | Cite as

Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells

  • Tom Moritz
  • Simone Venz
  • Heike Junker
  • Sarah Kreuz
  • Reinhard Walther
  • Uwe Zimmermann
Original Article


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.


PC-1 PrLZ TPD52 Neuroendocrine transdifferentiation Prostate cancer LNCaP 



We thank Robert Beyer and Sina Holstein for their contribution on experimental work. Special thanks go to Prof. Dr. Nicole Endlich (Department of Anatomy and Cell Biology, University Medicine Greifswald) for the opportunity to use microscopes for live cell imaging.

Compliance with Ethical Standards

The manuscript does not contain clinical studies, animal studies or patient data.

Conflicts of interest



  1. 1.
    Health report “Krebs in Deutschland 2009/2010, appeared 13.12.2013. Available from:
  2. 2.
    Byrne JA, Mattei MG, Basset P. Definition of the tumor protein D52 (TPD52) gene family through cloning of D52 homologues in human (hD53) and mouse (mD52). Genomics. 1996;35(3):523–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Byrne JA, et al. Identification of homo- and heteromeric interactions between members of the breast carcinoma-associated D52 protein family using the yeast two-hybrid system. Oncogene. 1998;16(7):873–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Byrne JA, et al. A screening method to identify genes commonly overexpressed in carcinomas and the identification of a novel complementary DNA sequence. Cancer Res. 1995;55(13):2896–903.PubMedGoogle Scholar
  5. 5.
    Visakorpi T, et al. Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res. 1995;55(2):342–7.PubMedGoogle Scholar
  6. 6.
    Wang R, et al. Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins. Biochem Biophys Res Commun. 2009;389(3):455–60.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen SL, et al. Isolation and characterization of a novel gene expressed in multiple cancers. Oncogene. 1996;12(4):741–51.PubMedGoogle Scholar
  8. 8.
    Wang R, et al. PrLZ, a novel prostate-specific and androgen-responsive gene of the TPD52 family, amplified in chromosome 8q21.1 and overexpressed in human prostate cancer. Cancer Res. 2004;64(5):1589–94.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang H, et al. PC-1/PrLZ contributes to malignant progression in prostate cancer. Cancer Res. 2007;67(18):8906–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Thomas DD, et al. A role for tumor protein TPD52 phosphorylation in endo-membrane trafficking during cytokinesis. Biochem Biophys Res Commun. 2010;402(4):583–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Thomas DD, et al. CRHSP-28 regulates Ca(2+)-stimulated secretion in permeabilized acinar cells. J Biol Chem. 2001;276(31):28866–72.CrossRefPubMedGoogle Scholar
  12. 12.
    Thomas DD, Weng N, Groblewski GE. Secretagogue-induced translocation of CRHSP-28 within an early apical endosomal compartment in acinar cells. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G253–63.CrossRefPubMedGoogle Scholar
  13. 13.
    Ummanni R, et al. Altered expression of tumor protein D52 regulates apoptosis and migration of prostate cancer cells. FEBS J. 2008;275(22):5703–13.CrossRefPubMedGoogle Scholar
  14. 14.
    Li L, et al. Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage. Carcinogenesis. 2013;34(2):257–67.CrossRefPubMedGoogle Scholar
  15. 15.
    Yu L, et al. PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability. Oncotarget. 2015;6(25):20356–69.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Edwards J, et al. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer. 2003;89(3):552–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lee YF, et al. Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells. Cancer Res. 2002;62(21):6039–44.PubMedGoogle Scholar
  18. 18.
    Montgomery RB, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–54.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Huss WJ, Gregory CW, Smith GJ. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate. 2004;60(2):91–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Jin RJ, et al. NE-10 neuroendocrine cancer promotes the LNCaP xenograft growth in castrated mice. Cancer Res. 2004;64(15):5489–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Bonkhoff H. Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate Suppl. 1998;8:18–22.CrossRefPubMedGoogle Scholar
  22. 22.
    Abrahamsson PA. Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer. 1999;6(4):503–19.CrossRefPubMedGoogle Scholar
  23. 23.
    Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma. Prostate. 1999;39(2):135–48.CrossRefPubMedGoogle Scholar
  24. 24.
    di Sant'Agnese PA, Cockett AT. Neuroendocrine differentiation in prostatic malignancy. Cancer. 1996;78(2):357–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Corcoran NM, Costello AJ. Interleukin-6: minor player or starring role in the development of hormone-refractory prostate cancer? BJU Int. 2003;91(6):545–53.CrossRefPubMedGoogle Scholar
  26. 26.
    Drachenberg DE, et al. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate. 1999;41(2):127–33.CrossRefPubMedGoogle Scholar
  27. 27.
    Nakashima J, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res. 2000;6(7):2702–6.PubMedGoogle Scholar
  28. 28.
    Deeble PD, et al. Interleukin-6- and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. Mol Cell Biol. 2001;21(24):8471–82.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mori R, et al. Gene profiling and pathway analysis of neuroendocrine transdifferentiated prostate cancer cells. Prostate. 2009;69(1):12–23.CrossRefPubMedGoogle Scholar
  30. 30.
    Hirano D, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol. 2004;45(5):586–92. discussion 592.CrossRefPubMedGoogle Scholar
  31. 31.
    Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate. 2004;61(4):332–53.CrossRefPubMedGoogle Scholar
  32. 32.
    Lottmann H, et al. The Tet-On system in transgenic mice: inhibition of the mouse pdx-1 gene activity by antisense RNA expression in pancreatic beta-cells. J Mol Med (Berl). 2001;79(5–6):321–8.CrossRefGoogle Scholar
  33. 33.
    Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992;89(12):5547–51.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Li L, et al. PrLZ expression is associated with the progression of prostate cancer LNCaP cells. Mol Carcinog. 2009;48(5):432–40.CrossRefPubMedGoogle Scholar
  35. 35.
    Ge D, et al. LNCaP prostate cancer cells with autocrine interleukin-6 expression are resistant to IL-6-induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling. Prostate. 2012;72(12):1306–16.CrossRefPubMedGoogle Scholar
  36. 36.
    Marchiani S, et al. Androgen-responsive and -unresponsive prostate cancer cell lines respond differently to stimuli inducing neuroendocrine differentiation. Int J Androl. 2010;33(6):784–93.CrossRefPubMedGoogle Scholar
  37. 37.
    Zelivianski S, et al. Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta. 2001;1539(1–2):28–43.CrossRefPubMedGoogle Scholar
  38. 38.
    Lee SO, et al. Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression. Prostate. 2007;67(7):764–73.CrossRefPubMedGoogle Scholar
  39. 39.
    Hobisch A, et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 1998;58(20):4640–5.PubMedGoogle Scholar
  40. 40.
    Wang J, et al. Identification and characterization of the novel human prostate cancer-specific PC-1 gene promoter. Biochem Biophys Res Commun. 2007;357(1):8–13.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang D, et al. PrLZ protects prostate cancer cells from apoptosis induced by androgen deprivation via the activation of Stat3/Bcl-2 pathway. Cancer Res. 2011;71(6):2193–202.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Bonkhoff H, et al. Relation of endocrine-paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate. Prostate. 1991;19(2):91–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Medical Biochemistry and Molecular BiologyErnst Moritz Arndt University of GreifswaldGreifswaldGermany
  2. 2.Laboratory of Chromatin Biochemistry, BESE DivisionKing Abdullah University of Science and TechnologyThuwalSaudi Arabia
  3. 3.Department of UrologyErnst Moritz Arndt University GreifswaldGreifswaldGermany

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