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RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

Feifei Sun1, Xinpei Wang1, Jing Hu2

  • 1The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China.

Oncogene
|May 4, 2022
PubMed

Insights

RuvB like AAA ATPase 1 (RUVBL1) upregulation promotes enzalutamide resistance in prostate cancer by activating the MAPK pathway. Inhibiting RUVBL1 may restore enzalutamide sensitivity and offer a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Enzalutamide improves survival in metastatic prostate cancer, but resistance (ENZR) is a significant clinical challenge.
  • Mechanisms driving ENZR beyond androgen receptor (AR) signaling are not fully understood.
  • Identifying novel pathways is crucial for overcoming treatment resistance.

Purpose of the Study:

  • To investigate the role of RuvB like AAA ATPase 1 (RUVBL1) in the development of enzalutamide resistance (ENZR) in prostate cancer (PCa).
  • To explore the molecular mechanisms by which RUVBL1 contributes to ENZR.
  • To evaluate RUVBL1 as a potential therapeutic target for overcoming enzalutamide resistance.

Main Methods:

  • Analysis of RUVBL1 expression in ENZR cells, xenograft models, and patient tumors.
  • Investigating the interaction between RUVBL1, CRAF, and plexin A1 (PLXNA1) in response to enzalutamide.
  • Assessing the effect of RUVBL1 inhibition using CB-6644 on PCa cell proliferation and xenograft growth.
  • Evaluating the re-sensitization of resistant cells to enzalutamide upon RUVBL1 inhibition.

Main Results:

  • RUVBL1 expression is upregulated in ENZR cells, xenografts, and patient tumors.
  • Enzalutamide treatment increases cytoplasmic RUVBL1, promoting CRAF recruitment to PLXNA1 and MAPK pathway activation.
  • Co-expression of RUVBL1 and PLXNA1 identifies a poor prognosis subgroup of PCa patients.
  • Pharmacological inhibition of RUVBL1 suppressed tumor growth and restored enzalutamide sensitivity.

Conclusions:

  • RUVBL1 acts as an alternative survival pathway, substituting for AR signaling in promoting ENZR.
  • RUVBL1 and its associated pathway (CRAF/PLXNA1/MAPK) are key drivers of enzalutamide resistance in prostate cancer.
  • Targeting RUVBL1 represents a promising therapeutic strategy for treating enzalutamide-resistant prostate cancer.

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