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Motexafin gadolinium enhances p53-Mdm2 interactions, reducing p53 and downstream targets in lymphoma cell lines
Amareshwar T K Singh1, Andrew M Evens, Sheila N Prachand
1Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. a-singh@northwestern.edu
Background:
Loss of p53 renders cells more susceptible to acute oxidant stress induced by oxidant-generating agents such as motexafin gadolinium (MGd). We hypothesized that reactive oxygen species (ROS)-generating MGd results in low-level p53 expression, making cells more susceptible to oxidant stress.
Materials And Methods:
Lymphoma cells were incubated with different concentrations of MGd with or without zinc (Zn) and ascorbate, and ROS, apoptosis, proteins, and oxidant genes were measured.
Results:
MGd, with ascorbate and Zn, induced apoptosis in lymphoma cells. This was accompanied by reduction of p53 protein but not message, and by reduction of p53 downstream targets p21, glutathione peroxidase 1 (GPx1), and p53 up-regulated modulator of apoptosis (PUMA). p53 protein reduction was reversed by MG132, and nutlin-3.
Conclusion:
Our data are consistent with a pathway of cell death that is independent of p53-mediated induction of PUMA; the cellular response to reduce p53 represents a cell survival adjustment to ROS-mediated stress.
Insights
Motexafin gadolinium (MGd) induces lymphoma cell death by reducing p53 protein, not message, suggesting a survival adjustment to reactive oxygen species (ROS) stress.
Area of Science:
- Cellular Biology
- Oxidative Stress Research
- Cancer Biology
Background:
- Loss of p53 tumor suppressor increases susceptibility to acute oxidant stress.
- Reactive oxygen species (ROS)-generating agents like motexafin gadolinium (MGd) may induce low-level p53 expression, enhancing cellular vulnerability.
- Understanding p53's role in oxidant stress is crucial for cancer therapy.
Purpose of the Study:
- To investigate the effect of ROS-generating MGd on p53 expression and lymphoma cell apoptosis.
- To determine if MGd-induced cell death is p53-dependent.
- To elucidate the cellular response to MGd-induced oxidative stress.
Main Methods:
- Lymphoma cells were treated with varying concentrations of MGd, with or without zinc (Zn) and ascorbate.
- Measurements included reactive oxygen species (ROS) levels, apoptosis, protein expression, and oxidant gene activity.
- p53 protein and message levels, as well as downstream targets like p21, GPx1, and PUMA, were analyzed.
Main Results:
- MGd, in combination with ascorbate and Zn, induced apoptosis in lymphoma cells.
- A reduction in p53 protein, but not its message, was observed.
- Downstream p53 targets (p21, GPx1, PUMA) were also reduced; p53 protein reduction was reversible with MG132 and nutlin-3.
Conclusions:
- The data suggest a cell death pathway independent of p53-mediated PUMA induction.
- The observed reduction in p53 protein represents a cell survival adjustment to ROS-mediated stress.
- This finding offers insights into cellular defense mechanisms against oxidative damage in cancer.
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