Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids
Autor: | Rameen Beroukhim, Nicholas L. Truex, Alexander R. Loftis, Xiaoli Liao, Bradley L. Pentelute, Zeyu Lu, Amy E. Rabideau, Meredith Brown, Brenton R. Paolella, John P. Busanovich |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Peptide Nucleic Acids Cell Survival Anthrax toxin Bacterial Toxins SF3B1 Gene 01 natural sciences Biochemistry Article 03 medical and health sciences Splicing factor Drug Delivery Systems Cell Line Tumor Neoplasms medicine Humans Viability assay Gene Antigens Bacterial Drug Carriers 010405 organic chemistry Chemistry Cancer General Medicine Genetic Therapy Oligonucleotides Antisense medicine.disease Phosphoproteins 0104 chemical sciences 030104 developmental biology Cancer cell Nucleic acid Cancer research Molecular Medicine RNA Splicing Factors |
Zdroj: | ACS Chem Biol PMC |
ISSN: | 1554-8937 |
Popis: | Copyright © 2020 American Chemical Society. Antisense oligonucleotide therapies are important cancer treatments, which can suppress genes in cancer cells that are critical for cell survival. SF3B1 has recently emerged as a promising gene target that encodes a key splicing factor in the SF3B protein complex. Over 10% of cancers have lost one or more copies of the SF3B1 gene, rendering these cancers vulnerable after further suppression. SF3B1 is just one example of a CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) gene, but over 120 additional candidate CYCLOPS genes are known. Antisense oligonucleotide therapies for cancer offer the promise of effective suppression for CYCLOPS genes, but developing these treatments is difficult due to their limited permeability into cells and poor cytosolic stability. Here, we develop an effective approach to suppress CYCLOPS genes by delivering antisense peptide nucleic acids (PNAs) into the cytosol of cancer cells. We achieve efficient cytosolic PNA delivery with the two main nontoxic components of the anthrax toxin: protective antigen (PA) and the 263-residue N-terminal domain of lethal factor (LFN). Sortase-mediated ligation readily enables the conjugation of PNAs to the C terminus of the LFN protein. LFN and PA work together in concert to translocate PNAs into the cytosol of mammalian cells. Antisense SF3B1 PNAs delivered with the LFN/PA system suppress the SF3B1 gene and decrease cell viability, particularly of cancer cells with partial copy-number loss of SF3B1. Moreover, antisense SF3B1 PNAs delivered with a HER2-binding PA variant selectively target cancer cells that overexpress the HER2 cell receptor, demonstrating receptor-specific targeting of cancer cells. Taken together, our efforts illustrate how PA-mediated delivery of PNAs provides an effective and general approach for delivering antisense PNA therapeutics and for targeting gene dependencies in cancer. |
Databáze: | OpenAIRE |
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