Protein-Programmed Accumulation of Yeast Cytosine Deaminase in Cancer Cells in Response to Mock-Hypoxia

Tiana D. Warren, Krishna Patel, James R. Eshleman, Marc Ostermeier

Research output: Contribution to journalArticle

Abstract

One limitation of gene-directed enzyme prodrug therapy (GDEPT) is the difficulty in selectively and efficiently transducing cancer cells with the gene encoding a prodrug-converting enzyme. To circumvent this issue, we sought to move the selectivity from the gene delivery level to the protein level. We developed fusion proteins of the prodrug-activating enzyme yeast cytosine deaminase (yCD) and the oxygen-dependent degradation domain (ODDD) of HIF-1α, a domain that regulates the accumulation of HIF-1α in an oxygen-dependent manner. We called these HOPE fusions for HIF1-α Oxygen-dependent degradation domain/Prodrug-converting Enzyme. The HOPE fusions were designed to selectively accumulate in cells experiencing hypoxia and thus selectively cause conversion of the prodrug 5-fluorocytosine (5-FC) to the chemotherapeutic 5-fluorouracil (5-FU) where oxygen levels are low (e.g., at the center of a tumor). Consistent with our hypothesis, HT1080 fibrosarcoma cells transduced with HOPE fusion genes exhibited increased fusion protein accumulation and increased sensitization to 5-FC in mock-hypoxia.

Original languageEnglish (US)
Pages (from-to)948-954
Number of pages7
JournalACS Synthetic Biology
Volume8
Issue number5
DOIs
StatePublished - May 17 2019

Keywords

  • GDEPT
  • HIF-1α
  • enzyme/prodrug therapy
  • protein engineering
  • yeast cytosine deaminase

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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