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Updated: Aug 1, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Pseurotin A Validation as a Metastatic Castration-Resistant Prostate Cancer Recurrence-Suppressing Lead via
Khaldoun S Abdelwahed1, Abu Bakar Siddique1, Hassan Y Ebrahim1
1School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Abstract:
Metastatic castration-resistant prostate cancer (mCRPC) cells can de novo biosynthesize their own cholesterol and overexpress proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 proved to contribute to mCRPC cell motility since PCSK9 knockdown (KD) in mCRPC CWR-R1ca cells led to notable reductions in cell migration and colony formation. Human tissue microarray results proved a higher immunohistoscore in patients ≥ 65 years old, and PCSK9 proved to be expressed higher at an early Gleason score of ≤7. The fermentation product pseurotin A (PS) suppressed PCSK9 expression, protein-protein interactions with LDLR, and breast and prostate cancer recurrences. PS suppressed migration and colony formation of the CWR-R1ca cells. The progression and metastasis of the CWR-R1ca-Luc cells subcutaneously (sc) xenografted into male nude mice fed a high-fat diet (HFD, 11% fat content) showed nearly 2-fold tumor volume, metastasis, serum cholesterol, low-density lipoprotein cholesterol (LDL-C), prostate-specific antigen (PSA), and PCSK9 levels versus mice fed a regular chow diet. Daily oral PS 10 mg/kg treatments prevented the locoregional and distant tumor recurrence of CWR-R1ca-Luc engrafted into nude mice after primary tumor surgical excision. PS-treated mice showed a significant reduction in serum cholesterol, LDL-C, PCSK9, and PSA levels. These results comprehensively validate PS as an mCRPC recurrence-suppressive lead by modulating the PCSK9-LDLR axis.
Insights
Pseurotin A (PS) suppresses prostate cancer recurrence by targeting PCSK9, a protein linked to cancer cell migration and cholesterol regulation. This compound reduces tumor growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) cells exhibit cholesterol biosynthesis and PCSK9 overexpression.
- PCSK9 is implicated in mCRPC cell motility, migration, and colony formation.
- Higher PCSK9 expression is observed in older patients (≥ 65 years) and those with lower Gleason scores (≤7).
Purpose of the Study:
- To investigate the role of PCSK9 in prostate cancer progression and metastasis.
- To evaluate the efficacy of pseurotin A (PS) in suppressing PCSK9 expression and mCRPC recurrence.
Main Methods:
- PCSK9 knockdown (KD) in mCRPC CWR-R1ca cells.
- Analysis of human tissue microarrays for PCSK9 expression.
- In vivo studies using CWR-R1ca-Luc xenografted mice on high-fat diet (HFD) treated with PS.
- Assessment of tumor volume, metastasis, serum markers (cholesterol, LDL-C, PSA, PCSK9), and recurrence post-surgery.
Main Results:
- PCSK9 KD significantly reduced mCRPC cell migration and colony formation.
- PS suppressed PCSK9 expression, LDLR interaction, and cancer recurrence in vivo.
- PS treatment in mice led to significant reductions in tumor progression, metastasis, and key serum markers (cholesterol, LDL-C, PSA, PCSK9).
Conclusions:
- Pseurotin A (PS) demonstrates significant potential as a therapeutic agent against mCRPC recurrence.
- PS effectively modulates the PCSK9-LDLR axis, impacting cholesterol metabolism and cancer cell behavior.
- These findings validate PS as a lead compound for developing novel mCRPC recurrence-suppressive therapies.
