Sustained cell growth, a hallmark of cancer, requires continuous protein synthesis that depends on an adequate supply of ribosomes. Transcription of ribosomal RNA is a rate-limiting step in ribosome biosynthesis. Inhibition of ribosomal RNA transcription is therefore an effective means to decrease ribosomal biogenesis thereby inhibiting cell growth. Angiogenin, whose concentration is elevated in many cancers, has recently been found by our group to undergo nuclear translocation in actively proliferating cells where it binds to the promoter region of the ribosomal RNA gene and stimulates rRNA transcription. The nuclear function of angiogenin is confined to proliferating cells that would include cancer cells and some normal cells only under certain circumstances such as during development and wound healing. The purpose of this exploratory/development grant application is to determine whether or not angiogenin is involved in transcription of ribosomal RNA in cancer cells and whether or not inhibition of angiogenin-enhanced rRNA synthesis can serve as a new molecular target for cancer drug development. Experiments are designed (1) to examine the nuclear translocation profile of angiogenin in cancer cells thereby determining the differential behavior of angiogenin in cancer and normal cells; (2) to investigate angiogenin-enhanced rRNA synthesis in cancer cells and its relationship with nuclear accumulation of endogenous as well as exogenous angiogenin; and (3) to inhibit nuclear translocation of angiogenin in cancer cells and determine the effect of this inhibition on rRNA synthesis, growth rate, and cell proliferation. Results obtained would determine whether it is feasible to develop anticancer drugs based on the intervention of the nuclear function of angiogenin.
