Structure-Guided Synthetic Peptide Targeting Nucleolus and Neural Progenitor Protein Nuclear Import Impairs Ribosome...

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Nucleolus and neural progenitor protein (NEPRO) is crucial for 40S ribosomal subunit maturation, supporting cancer cell proliferation.
• NEPRO's function is vital for meeting the high translational demands of rapidly dividing cancer cells.

Purpose of the Study:

• To investigate the nuclear localization signal (NLS) of NEPRO and its interaction with importin-α1.
• To develop a peptide-based inhibitor targeting NEPRO for cancer therapy.

Main Methods:

• Identification and characterization of NEPRO's bipartite NLS (aa 74-96).
• Analysis of a disease-associated mutation (R94C) and its effect on NEPRO nuclear import and importin-α1 binding.
• Design and synthesis of a hexapeptide inhibitor (AWPTPD) targeting the NEPRO NLS.
• In vitro and cellular assays to evaluate the peptide's efficacy in inhibiting NEPRO function and cancer cell growth.

Main Results:

• A disease mutation (R94C) in NEPRO's NLS disrupts nuclear localization and importin-α1 binding.
• The synthetic peptide AWPTPD specifically binds wild-type NEPRO and inhibits its nuclear import.
• Peptide treatment reduces polysome abundance, collagen secretion, and cancer cell clonogenicity, inducing cell-cycle arrest and senescence.

Conclusions:

• NEPRO's R94 residue is a critical target within its NLS for inhibiting nuclear import.
• A rationally designed peptide inhibitor can effectively disrupt ribosome biogenesis and suppress cancer cell proliferation.
• This peptide-based strategy offers a novel therapeutic approach for targeting cancer growth.