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ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling

Dalin He1, Lei Li2, Guodong Zhu1

  • 1Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Cancer Research
|June 14, 2014
PubMed

Insights

Men develop more kidney cancer (renal cell carcinoma, RCC) than women. This study found that the androgen receptor (AR) activates a HIF2α/VEGF pathway, driving RCC progression and offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Urology

Background:

  • Renal cell carcinoma (RCC) exhibits a higher incidence in males compared to females.
  • The underlying biological mechanisms for this observed gender disparity remain largely unknown.

Purpose of the Study:

  • To investigate the role of the androgen receptor (AR) in driving renal cell carcinoma (RCC) progression.
  • To elucidate the molecular signaling pathways involved in AR-mediated RCC development.
  • To identify potential therapeutic targets for mitigating gender-specific RCC progression.

Main Methods:

  • Utilized in vitro and in vivo models of RCC to assess the impact of AR modulation on cancer cell behavior.
  • Investigated the effects of AR attenuation and augmentation on RCC cell proliferation, migration, and invasion.
  • Analyzed the modulation of HIF2α/VEGF signaling at both mRNA and protein levels in response to AR targeting.
  • Evaluated the efficacy of HIF2α/VEGF inhibitors and the AR degradation enhancer ASC-J9 in suppressing RCC progression.

Main Results:

  • Androgen receptor (AR) activity was found to induce a HIF2α/VEGF signaling pathway crucial for RCC progression.
  • Modulation of AR levels significantly affected RCC cell proliferation, migration, and invasion in various experimental models.
  • Targeting AR inhibited RCC cell migration and invasion by regulating HIF2α/VEGF signaling at the molecular level.
  • Inhibition of HIF2α or VEGF, as well as the AR degrader ASC-J9, effectively suppressed RCC progression in vitro and in vivo.

Conclusions:

  • Discovered a novel role for the androgen receptor (AR) in the initiation and progression of renal cell carcinoma (RCC).
  • The AR-induced HIF2α/VEGF signaling pathway represents a critical mechanism underlying male predominance in RCC.
  • These findings suggest promising novel therapeutic strategies targeting the AR-HIF2α/VEGF axis for RCC treatment.

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