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

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Tumor Biology

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.

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Acknowledgement

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.

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    Authors and Affiliations

    1. Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany

      Tom Moritz, Simone Venz, Heike Junker, Sarah Kreuz & Reinhard Walther

    2. Laboratory of Chromatin Biochemistry, BESE Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia

      Sarah Kreuz

    3. Department of Urology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany

      Uwe Zimmermann

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    1. Tom Moritz
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    Correspondence to Heike Junker or Reinhard Walther.

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    Tom Moritz, Simone Venz and Heike Junker contributed equally to this work.

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    Moritz, T., Venz, S., Junker, H. et al. Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells. Tumor Biol. 37, 10435–10446 (2016). https://doi.org/10.1007/s13277-016-4925-1

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    • DOI: https://doi.org/10.1007/s13277-016-4925-1

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