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Ribonuclease inhibitor as an intracellular sentry
Marcia C Haigis1, Erin L Kurten, Ronald T Raines
1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544, USA.
Abstract:
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.
Insights
Onconase (ONC) and RNase A variants show increased toxicity in rapidly growing cells. Ribonuclease inhibitor protein (RI) constrains RNase A but not Onconase, offering insights for ribonuclease-based cancer chemotherapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Onconase (ONC), an RNase A homolog, is investigated as a cancer therapeutic.
- The efficacy of ONC and RNase A variants depends on evading the ribonuclease inhibitor protein (RI) to degrade cellular RNA.
Purpose of the Study:
- To investigate the relationship between cell growth rate and the cytotoxicity of ONC and RNase A variants.
- To determine the role of the ribonuclease inhibitor protein (RI) in modulating the cytotoxic effects of these ribonucleases.
Main Methods:
- Comparative analysis of cytotoxicity of ONC and RNase A variants in cells with varying growth rates.
- Assessment of RI levels in cells.
- Evaluation of RI overproduction effects on RNase A variant and ONC cytotoxicity.
Main Results:
- Cytotoxicity of both ONC and RNase A variants is enhanced in more rapidly growing cells.
- Endogenous RI levels remain constant across different cell growth rates.
- Overproducing RI reduces the potency of toxic RNase A variants but does not affect ONC cytotoxicity.
Conclusions:
- RI acts as a constraint on the cytotoxicity of RNase A variants.
- ONC's cytotoxicity is independent of RI levels, suggesting a different mechanism of action or evasion.
- These findings provide crucial insights for developing optimized ribonuclease-based cancer therapies.