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Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up-regulation of IRF1

Mayuko Kanayama1,2, Toshiya Hayano3, Michinori Koebis2

  • 1Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

The Prostate
|September 15, 2017
PubMed
Abstract

Insights

Active mammalian target of rapamycin (mTOR) induces neuroendocrine differentiation (NED) in prostate cancer, leading to cell growth arrest. This process involves interferon regulatory factor 1 (IRF1) and p21WAF1/CIP1, offering insights into NEPCa malignancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Neuroendocrine-differentiated prostate cancer (NEPCa) is aggressive and resistant to standard treatments.
  • Mechanisms driving NEPCa development, particularly neuroendocrine differentiation (NED), require further elucidation.
  • The role of mammalian target of rapamycin (mTOR) in NEPCa progression is not well understood.

Purpose of the Study:

  • To investigate the role of mTOR in inducing neuroendocrine differentiation (NED) in prostate cancer.
  • To identify key molecular players involved in mTOR-driven NED and associated malignant transformation.

Main Methods:

  • Established a human prostate cancer LNCaP cell line with hyperactive mTOR (LNCaP-mTOR) for gain-of-function analysis.
  • Utilized comprehensive mass spectrometry to identify transcription factors in LNCaP-mTOR cells.
  • Performed loss-of-function studies using CRISPR/Cas9 to assess the role of identified transcription factors.

Main Results:

  • mTOR activation successfully induced NED in prostate cancer cells.
  • NED was associated with significant cell growth arrest, mediated by increased p21WAF1/CIP1 expression.
  • Interferon regulatory factor 1 (IRF1) was identified as a key transcription factor driving growth arrest in NED via p21WAF1/CIP1.

Conclusions:

  • Active mTOR is a novel inducer of NED in prostate cancer.
  • A mechanism involving IRF1 and p21WAF1/CIP1 underlies mTOR-driven NED and malignant transformation in NEPCa.
  • This study provides in vitro evidence for the role of mTOR in NEPCa pathogenesis.
Keywords:
LNCaPNEDhyperactive mTORinterferon regulatory factor 1

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