Novel Peptide-1 targets Aurora-A, inhibiting prostate cancer cell proliferation and increasing p53/p21 expression.
Background
Prostate cancer remains a significant health challenge, with a need for novel therapeutic strategies, especially for advanced or resistant forms. Aurora-A kinase is a key regulator of cell division, and its overexpression is frequently observed in various cancers, including prostate cancer, correlating with aggressive disease and poor prognosis. Current treatments often face limitations due to resistance or systemic toxicity. Targeting Aurora-A offers a promising avenue to disrupt cancer cell proliferation, but specific and potent inhibitors with favorable profiles are still under investigation. This study explores a peptide-based approach to selectively inhibit Aurora-A.
Study Design
Researchers employed virtual screening to identify potential Aurora-A-targeting peptides. Among the candidates, Peptide-1 was selected for further characterization. Molecular docking and MST assays were used to evaluate binding affinity, revealing a dissociation constant (Kd). Conformational stability of the Aurora-A-Peptide-1 complex was assessed via MD simulation, MM/PBSA, and free-energy landscape analyses. Cellular antiproliferative activity was measured using MTT assays in PC3, DU145, NCI-H660 prostate cancer cells and RWPE-1 normal prostate cells. Aurora-A knockdown experiments confirmed target specificity, and qRT-PCR assessed changes in p53 and p21 mRNA expression in PC3/p53WT cells.
Results
Virtual screening identified four Aurora-A-targeting peptides, with Peptide-1 demonstrating the most favorable profile. > Molecular docking and MST assays confirmed that Peptide-1 exhibited the strongest binding affinity towards Aurora-A, with a dissociation constant (Kd) of 0.72 ± 0.04 μM. MD simulation, MM/PBSA, and free-energy landscape analyses indicated that the Aurora-A-Peptide-1 complex was conformationally stable, primarily driven by electrostatic interactions. MTT assays showed that Peptide-1 significantly inhibited the proliferation of PC3, DU145, and NCI-H660 prostate cancer cells, while showing weaker activity in RWPE-1 normal cells. Furthermore, Aurora-A knockdown reduced cellular sensitivity to Peptide-1, strongly supporting its target-dependent activity. qRT-PCR analysis revealed increased p53 and p21 mRNA expression after Peptide-1 treatment in PC3/p53WT cells, suggesting a mechanism involving cell cycle arrest and apoptosis pathways.
Why It Matters
This study introduces Peptide-1 as a promising novel agent for prostate cancer therapy by specifically targeting Aurora-A. The identification of a peptide with strong binding affinity and antiproliferative effects, coupled with its ability to upregulate p53 and p21, suggests a potent and potentially safer therapeutic strategy compared to small molecule inhibitors that may have off-target effects. Developing Aurora-A-targeting peptides could lead to more selective and effective treatments for prostate cancer, especially in cases where Aurora-A is overexpressed. While currently in the preclinical in-vitro stage, these findings lay the groundwork for future in-vivo studies and potential clinical translation, offering a new class of compounds for targeted oncology.