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

Nat Commun. 2020 Jan 20;11(1):384
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
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
+ et al

[No authors listed]

Author information
  • 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. bushra@iitk.ac.in.

摘要

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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