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Updated: Jul 29, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo
Junmei Liu1, Ranran Zhang2, Tong Su2
1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Background:
Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored.
Methods:
Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms.
Results:
PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells.
Conclusion:
Our data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.
Insights
Prohibitin (PHB1) is upregulated in castration-resistant prostate cancer (CRPC) and promotes resistance. The drug FL3 targets PHB1, suppressing CRPC growth and offering a new treatment strategy for ENZ-sensitive CRPC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Castration-resistant prostate cancer (CRPC) presents a significant therapeutic challenge.
- Prohibitin (PHB1), a protein upregulated in cancers, is implicated in tumor progression.
- The role of PHB1 in CRPC and the therapeutic potential of the drug FL3 remain underexplored.
Purpose of the Study:
- To investigate the role of PHB1 in prostate cancer (PCa) progression and castration resistance.
- To evaluate the anti-cancer effects of FL3 on CRPC cells and elucidate its underlying mechanisms.
- To explore PHB1 as a potential therapeutic target for CRPC.
Main Methods:
- Analysis of public datasets and human PCa specimens to correlate PHB1 expression with PCa progression and outcome.
- Gain/loss-of-function studies to determine PHB1's role in castration resistance.
- In vitro and in vivo experiments to assess FL3's efficacy and mechanisms in CRPC models.
Main Results:
- PHB1 expression is significantly elevated in CRPC, correlating with poor prognosis and promoting castration resistance.
- PHB1 expression and nuclear translocation are increased under androgen deprivation, suppressing androgen receptor (AR) signaling.
- FL3, alone or with enzalutamide (ENZ), effectively suppressed CRPC growth by modulating PHB1 trafficking, inhibiting AR and MAPK signaling, and promoting apoptosis.
Conclusions:
- Aberrant PHB1 upregulation in CRPC contributes to castration resistance.
- FL3 demonstrates therapeutic potential against CRPC, particularly ENZ-sensitive subtypes.
- Targeting PHB1 with FL3 offers a novel strategy for treating CRPC.
