Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer. Academic Article uri icon

Overview

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.

publication date

  • January 20, 2020

Research

keywords

  • Androgen Receptor Antagonists
  • Gene Expression Regulation, Neoplastic
  • Neuroendocrine Tumors
  • Prostatic Neoplasms
  • Trypsin Inhibitor, Kazal Pancreatic

Identity

PubMed Central ID

  • PMC6971084

Scopus Document Identifier

  • 85078284262

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-08-0979

PubMed ID

  • 31959826

Additional Document Info

volume

  • 11

issue

  • 1