Ribonuclease inhibitor as an intracellular sentry.
Onconase (ONC) is a homolog of RNase A that is in clinical trials as a cancer chemotherapeutic agent. The toxicity of ONC and RNase A variants relies on their ability to evade the cytosolic ribonuclease inhibitor protein (RI) and degrade cellular RNA. We find that these ribonucleases are more toxic for more rapidly growing cells. The enhanced cytotoxicity does not arise from variation in the endogenous level of RI, which is virtually constant. Overproduction of RI diminishes the potency of toxic RNase A variants, but has no effect on the cytotoxicity of ONC. Thus, RI constrains the cytotoxicity of RNase A. These data provide new insights for the development of an optimal ribonuclease-based cancer chemotherapy.
Haigis
Marcia C
MC
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544, USA.
Kurten
Erin L
EL
Raines
Ronald T
RT
D000970:Antineoplastic Agents / Q000633:toxicity*; D002352:Carrier Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D020128:Inhibitory Concentration 50; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012259:Ribonuclease, Pancreatic / Q000633:toxicity; D012260:Ribonucleases / Q000633:toxicity*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D011506:Proteins; C501467:RNH1 protein, human; D011993:Recombinant Fusion Proteins; D012260:Ribonucleases; D012259:Ribonuclease, Pancreatic; C058703:ranpirnase