PCSK9 Axis-Targeting Pseurotin A as a Novel Prostate Cancer Recurrence Suppressor Lead
Khaldoun S Abdelwahed1, Abu Bakar Siddique1, Mohammed H Qusa1
1School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, Louisiana 71201, United States.
Abstract:
Prostate cancer (PC) is the most common malignancy and the second leading cause of cancer death in men. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the cholesterol metabolism by regulating the LDL receptor (LDLR) degradation. The PCSK9 axis is proved to be a potential novel therapeutic target in multiple cancer types. Pseurotin A (PS) is a small-molecule natural-product inhibitor of PCSK9 expression and PCSK9-LDLR protein-protein interaction (PPI). The in vitro results of this study show that PS treatments caused dose-dependent suppression of migration, colony formation, and PCSK9 expression in the PC cell lines PC-3 and 22Rv1. PS suppressed the in vivo progression of PC-3 cells orthotopically xenografted in nude mice and prevented locoregional and distant tumor recurrences after primary tumor surgical excision. Western blot analysis showed decreased PCSK9 expression in collected primary and recurred PC-3 tumors in PS-treated mice. PS treatments also reduced the hemoglobin content in collected treated tumors and the Matrigel-plug angiogenesis mouse model. PS treatments prevented metastasis to distant organs compared to vehicle-treated control mice. A reduction in mice plasma cholesterol levels was observed. Microarray analysis of collected treated primary PC-3 tumors showed a distinct gene signature that confirmed the targeting of PCSK9 and cholesterol metabolism. Thus, the PCSK9 axis is proposed as a novel PC pathogenesis molecular target, and PS is defined as a novel effective PCSK9-targeting lead potentially useful for the control of the castration-resistant PC recurrence and metastasis.
Insights
Pseurotin A effectively targets the PCSK9 axis, inhibiting prostate cancer (PC) progression, recurrence, and metastasis. This natural compound shows promise for treating castration-resistant PC by impacting cholesterol metabolism and angiogenesis.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Prostate cancer (PC) is a leading cause of cancer death in men.
- The PCSK9 axis regulates cholesterol metabolism and is a potential therapeutic target in various cancers.
- Pseurotin A (PS) inhibits PCSK9 expression and PCSK9-LDLR protein-protein interaction.
Purpose of the Study:
- To investigate the efficacy of Pseurotin A (PS) in targeting the PCSK9 axis for prostate cancer (PC) treatment.
- To evaluate PS's effects on PC cell proliferation, migration, and angiogenesis.
- To assess PS's impact on PC recurrence, metastasis, and cholesterol metabolism.
Main Methods:
- In vitro studies using PC-3 and 22Rv1 cell lines.
- In vivo studies with orthotopically xenografted PC-3 cells in nude mice.
- Western blot, Matrigel-plug angiogenesis assay, and microarray analysis.
Main Results:
- PS dose-dependently suppressed PC cell migration, colony formation, and PCSK9 expression.
- PS inhibited tumor progression, recurrence, and metastasis in vivo, reducing tumor hemoglobin content.
- PS treatment led to decreased plasma cholesterol levels and a distinct gene signature confirming PCSK9 and cholesterol metabolism targeting.
Conclusions:
- The PCSK9 axis is a novel molecular target in prostate cancer pathogenesis.
- Pseurotin A is an effective PCSK9-targeting natural compound with potential for controlling castration-resistant PC recurrence and metastasis.
