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

Ritika Tiwari1, Nishat Manzar1, Vipul Bhatia1

  • 1Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India.

Nature Communications
|January 22, 2020
PubMed

Insights

Androgen receptor (AR) antagonists can increase SPINK1, promoting neuroendocrine prostate cancer (NEPC) by reducing AR-mediated repression. Casein Kinase-1 inhibition may offer a therapeutic strategy against this aggressive cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Androgen-deprivation therapy (ADT) can lead to aggressive neuroendocrine prostate cancer (NEPC).
  • SPINK1-positive prostate cancer is a recognized subtype.
  • AR antagonists are a common treatment for advanced prostate cancer.

Purpose of the Study:

  • To investigate the role of AR and its corepressor REST in regulating SPINK1 expression.
  • To explore the mechanism by which SPINK1 contributes to NEPC development.
  • To identify potential therapeutic strategies targeting SPINK1-mediated oncogenesis.

Main Methods:

  • Investigated the transcriptional regulation of SPINK1 by AR and REST.
  • Examined the role of SOX2 in SPINK1 activation during NE-transdifferentiation.
  • Utilized pharmacological inhibition of Casein Kinase-1.
  • Analyzed SPINK1 and NEPC marker expression in mouse models and patient tumors.

Main Results:

  • AR and REST repress SPINK1 transcription; AR antagonists alleviate this repression, upregulating SPINK1.
  • SOX2 transactivates SPINK1, promoting NE-phenotype, epithelial-mesenchymal-transition, stemness, and plasticity.
  • Casein Kinase-1 inhibition stabilizes REST, repressing SPINK1 and impeding oncogenesis.
  • Elevated SPINK1 and NEPC markers were observed in AR-antagonist treated mice and a subset of NEPC patients.

Conclusions:

  • SPINK1 upregulation, driven by AR antagonist treatment, may explain paradoxical clinical outcomes in prostate cancer after ADT.
  • SPINK1 plays a critical role in maintaining the NE-phenotype and promoting oncogenesis.
  • Targeting SPINK1 or enhancing AR/REST-mediated repression presents a potential adjuvant therapy strategy for NEPC.

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