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Updated: Sep 26, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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DAB2IP regulates intratumoral testosterone synthesis and CRPC tumor growth by ETS1/AKR1C3 signaling

Yanan Gu1, Shiqi Wu1, Yue Chong1

  • 1Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.

Cellular Signalling
|April 22, 2022
PubMed

Insights

Loss of DAB2IP promotes castration-resistant prostate cancer (CRPC) growth by enabling intratumoral androgen synthesis. This study identifies the DAB2IP/ETS1/AKR1C3 pathway as a potential therapeutic target for CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Intratumoral androgen synthesis reactivates androgen receptor (AR) in castration-resistant prostate cancer (CRPC).
  • Pathways controlling steroidogenic enzyme expression and de novo androgen synthesis in prostate cancer (PCa) remain largely unknown.
  • DAB2IP's role in regulating these pathways is unexplored.

Purpose of the Study:

  • To investigate the role of DAB2IP in regulating de novo androgen synthesis.
  • To explore the impact of DAB2IP on CRPC progression and tumor growth.
  • To identify potential therapeutic targets for CRPC based on androgen synthesis pathways.

Main Methods:

  • Investigated DAB2IP's effect on AR activity, PSA expression, and tumor growth in vitro and in vivo under castrated conditions.
  • Analyzed the expression profiles of steroidogenic enzymes, focusing on AKR1C3.
  • Elucidated the signaling pathway (PI3K/AKT/mTOR/ETS1) by which DAB2IP regulates AKR1C3 promoter activity and androgen synthesis.
  • Examined co-expression of ETS1 and AKR1C3 in PCa tissues and xenografts.
  • Assessed the effect of DHEA supplementation on AR nuclear staining in castrated DAB2IP-/- mice.

Main Results:

  • DAB2IP loss maintained AR transcriptional activity, PSA re-expression, and tumor growth in castrated conditions.
  • DAB2IP loss reprogrammed steroidogenic enzyme expression, notably increasing AKR1C3.
  • DAB2IP inhibited AKR1C3 promoter activity and testosterone synthesis from precursors via the PI3K/AKT/mTOR/ETS1 pathway.
  • High co-expression of ETS1 and AKR1C3 was observed in PCa tissues and xenografts.
  • DHEA supplementation restored AR nuclear staining in castrated DAB2IP-/- mice, indicating restored androgen synthesis.

Conclusions:

  • DAB2IP plays a crucial role in suppressing intratumoral de novo androgen synthesis in prostate cancer.
  • Loss of DAB2IP contributes to CRPC progression by promoting androgen synthesis and AR reactivation.
  • The DAB2IP/ETS1/AKR1C3 signaling axis represents a novel regulatory mechanism and a potential therapeutic target for CRPC.
Keywords:
AKR1C3Androgen synthesisCastration-resistant prostate cancerDAB2IPETS1

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