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Published on: July 20, 2019
Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression
Manuel Grima-Reyes1,2, Ashaina Vandenberghe1,2, Ivan Nemazanyy3
1Université Côte d'Azur, Inserm, C3M, Nice, France.
Abstract:
Depletion of circulating asparagine with l-asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U-13C5]-l-glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase's glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase's glutaminase activity should be considered in the clinic.
Insights
Asparagine depletion using l-asparaginase (ASNase) is key in leukemia therapy. Cancer cell sensitivity to ASNase is not solely predicted by asparagine synthetase (ASNS) levels, but also by ASNase
Area of Science:
- Biochemistry
- Oncology
- Cancer Biology
Background:
- L-asparaginase (ASNase) depletes circulating asparagine, a critical component in leukemia treatment.
- Asparagine synthetase (ASNS) expression levels were previously thought to predict cancer cell sensitivity to ASNase.
- Recent findings challenge the direct correlation between ASNS expression and ASNase efficacy.
Purpose of the Study:
- To investigate the role of asparagine synthetase (ASNS) expression in predicting cancer cell sensitivity to l-asparaginase (ASNase).
- To determine the impact of exogenous asparagine concentrations on de novo asparagine biosynthesis.
- To elucidate the contribution of ASNase's glutaminase activity to its anticancer effects.
Main Methods:
- In vitro and in vivo studies using [U-13C5]-l-glutamine.
- Utilized a mouse model of B cell lymphomas (BCLs).
- Assessed the effect of ASNS overexpression in ASNase-sensitive BCLs.
Main Results:
- Supraphysiological and physiological asparagine concentrations inhibit de novo asparagine biosynthesis irrespective of ASNS levels.
- Overexpression of ASNS did not confer resistance to ASNase treatment in vivo.
- ASNase's glutaminase activity is crucial for its maximal anticancer effect.
Conclusions:
- Baseline ASNS expression does not dictate BCL dependence on de novo asparagine biosynthesis or predict sensitivity to ASNase.
- ASNase's glutaminase activity is a significant factor in its clinical efficacy, particularly in ASNS-expressing cancers.
- The dual activity of ASNase should be considered for optimizing cancer therapy, except in ASNS-deficient cells.
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