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Hormone-Dependent Prostate Cancers are Dependent on Rac Signaling for Growth and Survival

Erik T Goka1, Dayrelis T Mesa Lopez1, Marc E Lippman2

  • 1Geneyus, LLC, Miami, Florida.

Molecular Cancer Therapeutics
|March 16, 2021
PubMed

Insights

Loss of HACE1 in prostate cancer leads to overactive Rac signaling, driving cancer growth. Inhibiting Rac1 slows cancer progression and enhances current androgen receptor therapies, offering new treatment strategies for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Prostate cancer (PC) is a leading cause of cancer death in men.
  • Initial PC therapies target androgen receptor (AR) signaling, but resistance leads to castration-resistant prostate cancer (CRPC).
  • The Rac1 signaling pathway is implicated in cancer progression.

Purpose of the Study:

  • To investigate the role of HACE1, an E3 ubiquitin ligase for Rac1, in prostate cancer.
  • To determine if targeting Rac1 can serve as an alternative therapeutic strategy for PC, including CRPC.

Main Methods:

  • Assessed HACE1 expression in prostate cancer tissues.
  • Investigated the impact of HACE1 loss on Rac1 activity and downstream signaling.
  • Evaluated the efficacy of a Rac1 inhibitor on prostate cancer cell proliferation, motility, and viability.
  • Examined the effect of Rac1 inhibition on AR signaling and AR target gene expression in androgen-dependent and CRPC models.

Main Results:

  • HACE1 is frequently lost in prostate cancer, leading to hyperactive Rac1 signaling.
  • Hyperactive Rac1 signaling promotes enhanced cellular proliferation, motility, and viability.
  • Rac1 inhibition effectively attenuates prostate cancer cell growth and survival.
  • Rac1 inhibition reduces AR target gene expression in androgen-dependent prostate cancer cells.
  • Combined Rac1 inhibition and AR antagonists synergistically suppress AR target gene expression.

Conclusions:

  • Loss of HACE1 and subsequent Rac1 hyperactivation is a key driver in prostate cancer progression.
  • Targeting Rac1 is a promising therapeutic strategy for prostate cancer, including CRPC.
  • Rac1 inhibition can enhance the efficacy of existing androgen receptor-targeted therapies.

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