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KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer

Lin Gao1, Wenbo Zhang1, Jing Zhang2

  • 1The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Cancer Research
|December 5, 2020
PubMed

Insights

Kinesin family member 15 (KIF15) drives enzalutamide resistance in prostate cancer by stabilizing androgen receptor (AR) signaling. Inhibiting KIF15 offers a new therapeutic strategy against resistant prostate tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Enzalutamide is a key treatment for metastatic prostate cancer, but resistance limits its efficacy.
  • Mechanisms underlying enzalutamide resistance in prostate cancer are not fully understood.
  • Androgen receptor (AR) signaling is central to prostate cancer progression and treatment resistance.

Purpose of the Study:

  • To investigate the role of kinesin family member 15 (KIF15) in enzalutamide resistance.
  • To elucidate the molecular mechanisms by which KIF15 confers resistance.
  • To evaluate KIF15 as a potential therapeutic target in enzalutamide-resistant prostate cancer.

Main Methods:

  • Investigated KIF15's interaction with androgen receptor (AR) and AR-V7.
  • Assessed the effect of KIF15 on AR/AR-V7 protein stability and degradation.
  • Utilized KIF15 inhibitors in combination with enzalutamide in cell culture and xenograft models.

Main Results:

  • KIF15 directly binds to AR/AR-V7, preventing its degradation via increased association with USP14.
  • AR signaling positively regulates KIF15 expression, creating a feedback loop.
  • KIF15 inhibition, alone or with enzalutamide, suppressed resistant prostate cancer cell growth and tumor progression.

Conclusions:

  • KIF15 is a critical mediator of enzalutamide resistance in prostate cancer.
  • Reciprocal activation between KIF15 and AR drives therapeutic resistance.
  • Co-targeting KIF15 and AR represents a promising therapeutic strategy for enzalutamide-resistant prostate cancer.

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