Anti-tumor effects of an engineered "killer" transfer RNA

Abstract

A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA(Ser)(AAU) is an engineered human tRNA(Ser) with an anticodon coding for isoleucine. Here we test the possibility that tRNA(Ser)(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA(Ser)(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA(Ser)(AAU) in both tumorigenic and non-tumorigenic cells. tRNA(Ser)(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA(Ser)(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA(Ser)(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA(Ser)(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.