2. Academic Validation
  3. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

  • Nat Commun. 2020 Jan 20;11(1):384. doi: 10.1038/s41467-019-14184-0.
Ritika Tiwari  # 1,  Nishat Manzar  # 1,  Vipul Bhatia 1,  Anjali Yadav 1,  Mushtaq A Nengroo 2,  Dipak Datta 2,  Shannon Carskadon 3,  Nilesh Gupta 4,  Michael Sigouros 5,  Francesca Khani 6,  Matti Poutanen 7,  Amina Zoubeidi 8,  Himisha Beltran 9,  Nallasivam Palanisamy 3,  Bushra Ateeq 10
Affiliations

Affiliations

  • 1 Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India.
  • 2 Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India.
  • 3 Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA.
  • 4 Department of Pathology, Henry Ford Health System, Detroit, MI, 48202, USA.
  • 5 Division of Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 6 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 7 Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.
  • 8 Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
  • 9 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 10 Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India. [email protected].
  • # Contributed equally.
PMID: 31959826 DOI: 10.1038/s41467-019-14184-0
Abstract

Emergence of an aggressive Androgen Receptor (AR)-independent neuroendocrine prostate Cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate Cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.

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